Gynecology_Novak

Gynecology_Novak. Although prolactin appears to be primarily under inhibitory control, many stimuli can elicit its release, including breast manipulation, drugs, stress, exercise, and certain foods. Hormones that may stimulate prolactin release include TRH, vasopressin, γ -aminobutyric acid (GABA), dopamine, β-endorphin, vasoactive intestinal peptide (VIP), epidermal growth factor, angiotensin II, and possibly GnRH (41–43). The relative contributions of these substances under normal conditions remain to be determined. Thyroid-Stimulating Hormone, Adrenocorticotropic Hormone, and Growth Hormone


Gynecology_Novak

Gynecology_Novak. Thyroid-Stimulating Hormone, Adrenocorticotropic Hormone, and Growth Hormone The other hormones produced by the anterior pituitary are TSH, ACTH, and GH. Thyroid-stimulating hormone is secreted by the pituitary thyrotrophs in response to TRH. As with GnRH, TRH is synthesized primarily in the arcuate nucleus of the hypothalamus and is secreted into the portal circulation for transport to the pituitary. In addition to stimulating TSH release, TRH is a major stimulus for the release of prolactin. Thyroid-stimulating hormone stimulates release of T3 and T4 from the thyroid gland, which in turn has a negative feedback effect on pituitary TSH secretion. Abnormalities of thyroid secretion (both hyper-and hypothyroidism) are frequently associated with ovulatory dysfunction as a result of diverse actions on the hypothalamic–pituitary–ovarian axis (44).


Gynecology_Novak

Gynecology_Novak. Adrenocorticotrophic hormone is secreted by the anterior pituitary in response to another hypothalamic-releasing factor, CRH, and stimulates the release of adrenal glucocorticoids. Unlike the other anterior pituitary products, ACTH secretion has a diurnal variation with an early morning peak and a late evening nadir. As with the other pituitary hormones, ACTH secretion is negatively regulated by feedback from its primary end product, which in this case is cortisol.


Gynecology_Novak

Gynecology_Novak. The anterior pituitary hormone that is secreted in the greatest absolute amount is GH. It is secreted in response to the hypothalamic-releasing factor, GHRH, and by thyroid hormone and glucocorticoids. This hormone is secreted in a pulsatile fashion but with peak release occurring during sleep. In addition to its vital role in the stimulation of linear growth, GH plays a diverse role in physiologic hemostasis. The hormone plays a role in bone mitogenesis, CNS function (improved memory, cognition, and mood), body composition, breast development, and cardiovascular function. It also affects insulin regulation and acts anabolically. Growth hormone appears to have a role in the regulation of ovarian function, although the degree to which it serves this role in normal physiology is unclear (45).


Gynecology_Novak

Gynecology_Novak. The posterior pituitary (neurohypophysis) is composed exclusively of neural tissue and is a direct extension of the hypothalamus. It lies directly adjacent to the adenohypophysis but is embryologically distinct, derived from an invagination of neuroectodermal tissue in the third ventricle. Axons in the posterior pituitary originate from neurons with cell bodies in two distinct regions of the hypothalamus, the supraoptic and paraventricular nuclei, named for their anatomic relationship to the optic chiasm and the third ventricle. Together these two nuclei compose the hypothalamic magnocellular system. These neurons can secrete their synthetic products directly from axonal boutons into the general circulation to act as hormones. This is the mechanism of secretion of the hormones of the posterior pituitary, oxytocin and arginine vasopressin (AVP). Although this is the primary mode of release for these hormones, numerous other secondary pathways were identified, including secretion into


Gynecology_Novak

Gynecology_Novak. pituitary, oxytocin and arginine vasopressin (AVP). Although this is the primary mode of release for these hormones, numerous other secondary pathways were identified, including secretion into the portal circulation, intrahypothalamic secretion, and secretion into other regions of the CNS (46).


Gynecology_Novak

Gynecology_Novak. In addition to the established functions of oxytocin and vasopressin, several other diverse roles were suggested in animal models. These functions include modulation of sexual activity and appetite, learning and memory consolidation, temperature regulation, and regulation of maternal behaviors (47). In the human, these neuropeptides were linked to social attachment (48–50). Receptor variants for these two molecules were linked to the spectrum of autistic disorders, suggesting that proper function of these two neuropeptides with their receptors is required for positive group interactive behavior. This relationship is strengthened by a strong association between altruistic behavior and the length of the AVP-1a receptor promoter region (51). It is both surprising and humbling that complex human behaviors may be partially explained by such a relatively simple neuropeptide system. Continuing investigation should help elucidate this physiology and potential therapeutic interventions.


Gynecology_Novak

Gynecology_Novak. Oxytocin Oxytocin is a 9–amino acid peptide primarily produced by the paraventricular nucleus of the hypothalamus (Fig. 7.7). The primary function of this hormone in humans is the stimulation of two specific types of muscular contractions (Fig. 7.8). The first type, uterine muscular contraction, occurs during parturition. The second type of muscular contraction regulated by oxytocin is breast lactiferous duct myoepithelial contractions, which occur during the milk letdown reﬂex. Oxytocin release may be stimulated by suckling, triggered by a signal from nipple stimulation transmitted via thoracic nerves to the spinal cord and then to the hypothalamus, where oxytocin is released in an episodic fashion (45). Oxytocin release also may be triggered by olfactory, auditory, and visual clues, and it may play a role in the conditioned reﬂex in nursing animals. Stimulation of the cervix and vagina can cause significant release of oxytocin, which may trigger reﬂex ovulation (the Ferguson reﬂex)


Gynecology_Novak

Gynecology_Novak. it may play a role in the conditioned reﬂex in nursing animals. Stimulation of the cervix and vagina can cause significant release of oxytocin, which may trigger reﬂex ovulation (the Ferguson reﬂex) in some species.


Gynecology_Novak

Gynecology_Novak. Figure 7.7 Oxytocin and arginine-vasopressin (AVP) are 9–amino acid peptides produced by the hypothalamus. They differ in only two amino acids. Figure 7.8 Oxytocin stimulates muscular contractions of the uterus during parturition and the breast lactiferous duct during the milk letdown reﬂex. Arginine-vasopressin (AVP) regulates circulating blood volume, pressure, and osmolality.


Gynecology_Novak

Gynecology_Novak. Arginine Vasopressin Also known as antidiuretic hormone (ADH), AVP is the second major secretory product of the posterior pituitary (Fig. 7.7). It is synthesized primarily by neurons with cell bodies in the supraoptic nuclei (Fig. 7.8). Its major function is the regulation of circulating blood volume, pressure, and osmolality (52). Specific receptors throughout the body can trigger the release of AVP. Osmoreceptors located in the hypothalamus sense changes in blood osmolality from a mean of 285 mOSM/kg. Baroceptors sense changes in blood pressure caused by alterations in blood volume and are peripherally located in the walls of the left atrium, carotid sinus, and aortic arch (53). These receptors can respond to changes in blood volume of more than 10%. In response to decreases in blood pressure or volume, AVP is released and causes arteriolar vasoconstriction and renal free-water conservation. This in turn leads to a decrease in blood osmolality and an increase in blood pressure.


Gynecology_Novak

Gynecology_Novak. pressure or volume, AVP is released and causes arteriolar vasoconstriction and renal free-water conservation. This in turn leads to a decrease in blood osmolality and an increase in blood pressure. Activation of the renal renin–angiotensin system can also activate AVP release.


Gynecology_Novak

Gynecology_Novak. In the normal menstrual cycle, orderly cyclic hormone production and parallel proliferation of the uterine lining prepare for implantation of the embryo. Disorders of the menstrual cycle and, likewise, disorders of menstrual physiology, may lead to various pathologic states, including infertility, recurrent miscarriage, and malignancy.


Gynecology_Novak

Gynecology_Novak. The normal human menstrual cycle can be divided into two segments: the ovarian cycle and the uterine cycle, based on the organ under examination. The ovarian cycle may be further divided into follicular and luteal phases, whereas the uterine cycle is divided into corresponding proliferative and secretory phases (Fig. 7.9). The phases of the ovarian cycle are characterized as follows: 1. Follicular phase—hormonal feedback promotes the orderly development of a single dominant follicle, which should be mature at midcycle and prepared for ovulation. The average length of the human follicular phase ranges from 10 to 14 days, and variability in this length is responsible for most variations in total cycle length.


Gynecology_Novak

Gynecology_Novak. Figure 7.9 The menstrual cycle. The top panel shows the cyclic changes of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P) relative to the time of ovulation. The bottom panel correlates the ovarian cycle in the follicular and luteal phases and the endometrial cycle in the proliferative and secretory phases. 2. Luteal phase—the time from ovulation to the onset of menses has an average length of 14 days. A normal menstrual cycle lasts from 21 to 35 days, with 2 to 6 days of ﬂow and an average blood loss of 20 to 60 mL. However, studies of large numbers of women with normal menstrual cycles showed that only approximately two-thirds of adult women have cycles lasting 21 to 35 days (54). The extremes of reproductive life (after menarche and perimenopause) are characterized by a higher percentage of anovulatory or irregularly timed cycles (55,56).


Gynecology_Novak

Gynecology_Novak. Hormonal Variations The relative pattern of ovarian, uterine, and hormonal variation along the normal menstrual cycle is shown in Fig. 7.9. 1. At the beginning of each monthly menstrual cycle, levels of gonadal steroids are low and have been decreasing since the end of the luteal phase of the previous cycle. 2. With the demise of the corpus luteum, FSH levels begin to rise, and a cohort of growing follicles is recruited. These follicles each secrete increasing levels of estrogen as they grow in the follicular phase. The increase in estrogen, in turn, is the stimulus for uterine endometrial proliferation. 3.


Gynecology_Novak

Gynecology_Novak. 3. Rising estrogen levels provide negative feedback on pituitary FSH secretion, which begins to wane by the midpoint of the follicular phase. In addition, the growing follicles produce inhibin-B, which suppresses FSH secretion by the pituitary. Conversely, LH initially decreases in response to rising estradiol levels, but late in the follicular phase the LH level is increased dramatically (biphasic response). 4. At the end of the follicular phase (just before ovulation), FSH-induced LH receptors are present on granulosa cells and, with LH stimulation, modulate the secretion of progesterone. 5. After a sufficient degree of estrogenic stimulation, the pituitary LH surge is triggered, which is the proximate cause of ovulation that occurs 24 to 36 hours later. Ovulation heralds the transition to the luteal–secretory phase. 6.


Gynecology_Novak

Gynecology_Novak. Ovulation heralds the transition to the luteal–secretory phase. 6. The estrogen level decreases through the early luteal phase from just before ovulation until the midluteal phase, when it begins to rise again as a result of corpus luteum secretion. Similarly, inhibin-A is secreted by the corpus luteum. 7. Progesterone levels rise precipitously after ovulation and can be used as a presumptive sign that ovulation has occurred. 8. Progesterone, estrogen, and inhibin-A act centrally to suppress gonadotropin secretion and new follicular growth. These hormones remain elevated through the lifespan of the corpus luteum and then wane with its demise, thereby setting the stage for the next cycle. Cyclic Changes of the Endometrium


Gynecology_Novak

Gynecology_Novak. Cyclic Changes of the Endometrium In 1950, Noyes, Hertig, and Rock described the cyclic histologic changes in the adult human endometrium (57) (Fig. 7.10). These changes proceed in an orderly fashion in response to cyclic hormonal production by the ovaries (Fig. 7.9). Histologic cycling of the endometrium can best be viewed in two parts: the endometrial glands and the surrounding stroma. The superficial two-thirds of the endometrium is the zone that proliferates and is ultimately shed with each cycle if pregnancy does not occur. This cycling portion of the endometrium is known as the decidua functionalis and is composed of a deeply situated intermediate zone (stratum spongiosum) and a superficial compact zone (stratum compactum). The decidua basalis is the deepest region of the endometrium. It does not undergo significant monthly proliferation but, instead, is the source of endometrial regeneration after each menses (58).


Gynecology_Novak

Gynecology_Novak. The existence of endometrial stem cells was assumed but difficult to document. Researchers found a small population of human epithelial and stromal cells that possess clonogenicity, suggesting that they represent the putative endometrial stem cells (59). Further evidence of the existence of such cells, and their source, was provided by another study that showed endometrial glandular epithelial cells obtained from endometrial biopsies of women undergoing bone marrow transplants, express the HLA type of the donor bone marrow (60). This finding suggests that endometrial stem cells exist, and that they reside in bone marrow and migrate to the basalis of the endometrium. Furthermore, the timing of the appearance of these cells following the transplant was as long as several years. This fact may prove to be of clinical importance in patients with Asherman syndrome who experienced a loss of functional endometrium; repair of the uterine anatomy may eventually result in a functioning


Gynecology_Novak

Gynecology_Novak. fact may prove to be of clinical importance in patients with Asherman syndrome who experienced a loss of functional endometrium; repair of the uterine anatomy may eventually result in a functioning endometrial cavity.


Gynecology_Novak

Gynecology_Novak. Figure 7.10 The number of oocytes in the ovary before and after birth and through menopause.


Gynecology_Novak

Gynecology_Novak. By convention, the first day of vaginal bleeding is called day 1 of the menstrual cycle. After menses, the decidua basalis is composed of primordial glands and dense scant stroma in its location adjacent to the myometrium. The proliferative phase is characterized by progressive mitotic growth of the decidua functionalis in preparation for implantation of the embryo in response to rising circulating levels of estrogen (61). At the beginning of the proliferative phase, the endometrium is relatively thin (1–2 mm). The predominant change seen during this time is evolution of the initially straight, narrow, and short endometrial glands into longer, tortuous structures (62). Histologically, these proliferating glands have multiple mitotic cells, and their organization changes from a low columnar pattern in the early proliferative period to a pseudostratified pattern before ovulation. Throughout this time, the stroma is a dense compact layer, and vascular structures are infrequently seen.


Gynecology_Novak

Gynecology_Novak. In the typical 28-day cycle, ovulation occurs on cycle day 14. Within 48 to 72 hours following ovulation, the onset of progesterone secretion produces a shift in histologic appearance of the endometrium to the secretory phase, so named for the clear presence of eosinophilic protein-rich secretory products in the glandular lumen. In contrast to the proliferative phase, the secretory phase of the menstrual cycle is characterized by the cellular effects of progesterone in addition to estrogen. In general, progesterone’s effects are antagonistic to those of estrogen, and there is a progressive decrease in the endometrial cell’s estrogen receptor concentration. As a result, during the latter half of the cycle, estrogen-induced DNA synthesis and cellular mitosis are antagonized (61).


Gynecology_Novak

Gynecology_Novak. During the secretory phase, the endometrial glands form characteristic periodic acid–Schiff positive–staining, glycogen-containing vacuoles. These vacuoles initially appear subnuclearly and then progress toward the glandular lumen (57) (Fig. 7.10). The nuclei can be seen in the midportion of the cells and ultimately undergo apocrine secretion into the glandular lumen, often by cycle day 19 or 20. At postovulatory day 6 or 7, secretory activity of the glands is generally maximal, and the endometrium is optimally prepared for implantation of the blastocyst.


Gynecology_Novak

Gynecology_Novak. The stroma of the secretory phase remains unchanged histologically until approximately the seventh postovulatory day, when there is a progressive increase in edema. Coincident with maximal stromal edema in the late secretory phase, the spiral arteries become clearly visible and then progressively lengthen and coil during the remainder of the secretory phase. By around day 24, an eosinophilic-staining pattern, known as cuffing, is visible in the perivascular stroma. Eosinophilia then progresses to form islands in the stroma followed by areas of conﬂuence. This staining pattern of the edematous stroma is termed pseudodecidual because of its similarity to the pattern that occurs in pregnancy. Approximately 2 days before menses, there is a dramatic increase in the number of polymorphonuclear lymphocytes that migrate from the vascular system. This leukocytic infiltration heralds the collapse of the endometrial stroma and the onset of the menstrual ﬂow.


Gynecology_Novak

Gynecology_Novak. In the absence of implantation, glandular secretion ceases and an irregular breakdown of the decidua functionalis occurs. The resultant shedding of this layer of the endometrium is termed menses. The destruction of the corpus luteum and its production of estrogen and progesterone is the presumed cause of the shedding. With withdrawal of sex steroids, there is a profound spiral artery vascular spasm that ultimately leads to endometrial ischemia. Simultaneously, there is a breakdown of lysosomes and a release of proteolytic enzymes, which further promote local tissue destruction. This layer of endometrium is then shed, leaving the decidua basalis as the source of subsequent endometrial growth. Prostaglandins are produced throughout the menstrual cycle and are at their highest concentration during menses (60). Prostaglandin F2α (PGF2α) is a potent vasoconstrictor, causing further arteriolar vasospasm and endometrial ischemia. PGF2α produces myometrial contractions that decrease local


Gynecology_Novak

Gynecology_Novak. during menses (60). Prostaglandin F2α (PGF2α) is a potent vasoconstrictor, causing further arteriolar vasospasm and endometrial ischemia. PGF2α produces myometrial contractions that decrease local uterine wall blood ﬂow and may serve to expel physically the sloughing endometrial tissue from the uterus.


Gynecology_Novak

Gynecology_Novak. Dating the Endometrium The changes seen in secretory endometrium relative to the LH surge were thought to allow the assessment of the “normalcy” of endometrial development. Since 1950, it was felt that by knowing when a patient ovulated, it was possible to obtain a sample of endometrium by endometrial biopsy and determine whether the state of the endometrium corresponds to the appropriate time of the cycle. Traditional thinking held that any discrepancy of more than 2 days between chronologic and histologic date indicated a pathologic condition termed luteal phase defect; this abnormality was linked to both infertility (via implantation failure) and early pregnancy loss (63).


Gynecology_Novak

Gynecology_Novak. Evidence suggests a lack of utility for the endometrial biopsy as a diagnostic test for either infertility or early pregnancy loss (56). In a randomized, observational study of regularly cycling, fertile women, it was found that endometrial dating is far less accurate and precise than originally claimed and does not provide a valid method for the diagnosis of luteal phase defect (64). Furthermore, a large prospective, multicenter trial sponsored by the National Institutes of Health showed that histologic dating of the endometrium does not discriminate between fertile and infertile women (65). Thus, after half a century of using this test in the evaluation of the subfertile couple, it became clear that the endometrial biopsy has no role in the routine evaluation of infertility or early pregnancy loss.


Gynecology_Novak

Gynecology_Novak. The number of oocytes peaks in the fetus at 6 to 7 million by 20 weeks of gestation (66) (Fig. 7.10). Simultaneously (and peaking at the 5th month of gestation), atresia of the oogonia occurs, rapidly followed by follicular atresia. At birth, only 1 to 2 million oocytes remain in the ovaries, and at puberty, only 300,000 of the original 6 to 7 million oocytes are available for ovulation (66,67). Of these, only 400 to 500 will ultimately be released during ovulation. By the time of menopause, the ovary will be composed primarily of dense stromal tissue with only rare interspersed oocytes remaining.


Gynecology_Novak

Gynecology_Novak. A central dogma of reproductive biology is that in mammalian females there is no capacity for oocyte production postnatally. Because oocytes enter the diplotene resting stage of meiosis in the fetus and persist in this stage until ovulation, much of the DNA, proteins, and messenger RNA (mRNA) necessary for development of the preimplantation embryo is synthesized by this stage. At the diplotene stage, a single layer of 8 to 10 granulosa cells surround the oogonia to form the primordial follicle. The oogonia that fail to become properly surrounded by granulosa cells undergo atresia (68). The remainder proceeds with follicular development. Thus, most oocytes are lost during fetal development, and the remaining follicles are steadily “used up” throughout the intervening years until menopause.


Gynecology_Novak

Gynecology_Novak. Evidence has begun to challenge this theory. Studies in the mouse showed that production of oocytes and corresponding folliculogenesis can occur well into adult life (69). The reservoir of germline stem cells responsible for this oocyte development appears to reside in the bone marrow (70). It is not clear whether such stem cells exist in adult humans, and if they do, what clinical function they might provide. Meiotic Arrest of Oocyte and Resumption Meiosis (the germ cell process of reduction division) is divided into four phases: prophase, metaphase, anaphase, and telophase. The prophase of meiosis I is further divided into five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis.


Gynecology_Novak

Gynecology_Novak. Oogonia differ from spermatogonia in that only one final daughter cell (oocyte) forms from each precursor cell, with the excess genetic material discarded in three polar bodies. When the developing oogonia begin to enter meiotic prophase I, they are known as primary oocytes (71). This process begins at roughly 8 weeks of gestation. Only those oogonia that enter meiosis will survive the wave of atresia that sweeps the fetal ovary before birth. The oocytes arrested in prophase (in the late diplotene or “dictyate” stage) will remain so until the time of ovulation, when the process of meiosis resumes. The mechanism for this mitotic stasis is believed to be an oocyte maturation inhibitor (OMI) produced by granulosa cells (72). This inhibitor gains access to the oocyte via gap junctions connecting the oocyte and its surrounding cumulus of granulosa. With the midcycle LH surge, the gap junctions are disrupted, granulosa cells are no longer connected to the oocyte, and meiosis I is allowed to


Gynecology_Novak

Gynecology_Novak. the oocyte and its surrounding cumulus of granulosa. With the midcycle LH surge, the gap junctions are disrupted, granulosa cells are no longer connected to the oocyte, and meiosis I is allowed to resume.


Gynecology_Novak

Gynecology_Novak. Follicular Development Follicular development is a dynamic process that continues from menarche until menopause. The process is designed to allow the monthly recruitment of a cohort of follicles and, ultimately, to release a single, mature, dominant follicle during ovulation each month.


Gynecology_Novak

Gynecology_Novak. The initial recruitment and growth of the primordial follicles is gonadotropin independent and affects a cohort over several months (73). The stimuli responsible for the recruitment of a specific cohort of follicles in each cycle are unknown. At the primordial follicle stage, shortly after initial recruitment, FSH assumes control of follicular differentiation and growth and allows a cohort of follicles to continue differentiation. This process signals the shift from gonadotropin-independent to gonadotropin-dependent growth. The first changes seen are growth of the oocyte and expansion of the single layer of follicular granulosa cells into a multilayer of cuboidal cells. The decline in luteal phase estrogen, progesterone, and inhibin-A production by the now-fading corpus luteum from the previous cycle allows the increase in FSH that stimulates this follicular growth (74).


Gynecology_Novak

Gynecology_Novak. During the several days following the breakdown of the corpus luteum, growth of the cohort of follicles continues, driven by the stimulus of FSH. The enlarging oocyte secretes a glycoprotein-rich substance, the zona pellucida, which separates it from the surrounding granulosa cells (except for the aforementioned gap junction). With transformation from a primordial to a preantral follicle, there is continued mitotic proliferation of the encompassing granulosa cells. Simultaneously, theca cells in the stroma bordering the granulosa cells proliferate. Both cell types function synergistically to produce estrogens that are secreted into the systemic circulation. At this stage of development, each of the seemingly identical cohort members must either be selected for dominance or undergo atresia. It is likely that the follicle destined to ovulate was selected before this point, although the mechanism for selection remains obscure. Two-Cell, Two-Gonadotropin Theory


Gynecology_Novak

Gynecology_Novak. Two-Cell, Two-Gonadotropin Theory The fundamental tenet of follicular development is the two-cell, two-gonadotropin theory (73,75,76) (Fig. 7.11). This theory states that there is a subdivision and compartmentalization of steroid hormone synthesis activity in the developing follicle. Most aromatase activity (for estrogen production) is in the granulosa cells (77). Aromatase activity is enhanced by FSH stimulation of specific receptors on these cells (78,79). Granulosa cells lack several enzymes that Figure 7.11 The two-cell, two-gonadotropin theory of follicular development in which there is compartmentalization of steroid hormone synthesis in the developing follicle. LH, luteinizing hormone; FSH, follicle-stimulating hormone.


Gynecology_Novak

Gynecology_Novak. occur earlier in the steroidogenic pathway and require androgens as a substrate for aromatization. Androgens, in turn, are synthesized primarily in response to stimulation by LH, and the theca cells possess most of the LH receptors at this stage (78,79). Therefore, a synergistic relationship must exist: LH stimulates the theca cells to produce androgens (primarily androstenedione), which in turn are transferred to the granulosa cells for FSH-stimulated aromatization into estrogens. These locally produced estrogens create a microenvironment within the follicle that is favorable for continued growth and nutrition (80). Both FSH and local estrogens serve to further stimulate estrogen production, FSH receptor synthesis and expression, and granulosa cell proliferation and differentiation.


Gynecology_Novak

Gynecology_Novak. Androgens have two positive regulatory roles in follicular development. Within the ovary, androgens promote granulose cell proliferation, aromatase activity, and inhibit programmed death of these cells (81). As the peripheral estrogen level rises, it negatively feeds back on the pituitary and hypothalamus to decrease circulating FSH levels (82). Increased ovarian production of inhibin-B further decreases FSH production at this point.


Gynecology_Novak

Gynecology_Novak. The falling FSH level that occurs with the progression of the follicular phase represents a threat to continued follicular growth. The resulting adverse environment can be withstood only by follicles with a selective advantage for binding the diminishing FSH molecules; that is, those with the greatest number of FSH receptors. The dominant follicle, therefore, can be perceived as the one with a richly estrogenic microenvironment and the most FSH receptors (83). As it grows and develops, the follicle continues to produce estrogen, which results in further lowering of the circulating FSH and creates a more adverse environment for competing follicles. This process continues until all members of the initial cohort, with the exception of the single dominant follicle, have suffered atresia. The stage is then set for ovulation.


Gynecology_Novak

Gynecology_Novak. Chronic elevation of androgens suppresses hypothalamic–pituitary secretion of FSH, a detriment to the development and maturation of a dominant follicle (81). Clinically, androgen excess results in chronic anovulation, as is seen in polycystic ovarian syndrome. Preovulatory follicles are characterized by a ﬂuid-filled antrum that is composed of plasma with granulosa cell secretions. The granulosa cells at this point have further differentiated into a heterogenous population. The oocyte remains connected to the follicle by a stalk of specialized granulosa known as the cumulus oophorus.


Gynecology_Novak

Gynecology_Novak. Rising estrogen levels have a negative feedback effect on FSH secretion. Conversely, LH undergoes biphasic regulation by circulating estrogens. At lower concentrations, estrogens inhibit LH secretion. At higher levels, estrogen enhances LH release. This stimulation requires a sustained high level of estrogen (200 pg/mL) for more than 48 hours (84). Once the rising estrogen level produces positive feedback, a substantial surge in LH secretion occurs. Concomitant to these events, the local estrogen–FSH interactions in the dominant follicle induce LH receptors on the granulosa cells. Exposure to high levels of LH results in a specific response by the dominant follicle—the result is luteinization of the granulosa cells, production of progesterone, and initiation of ovulation. Ovulation will occur in the single mature, or Graafian, follicle 10 to 12 hours after the LH peak or 34 to 36 hours after the initial rise in midcycle LH (85–87).


Gynecology_Novak

Gynecology_Novak. As suggested previously, the sex steroids are not the only gonadotropin regulators of follicular development. Two related granulosa cell–derived peptides were identified that play opposing roles in pituitary feedback (88). The first of these peptides, inhibin, is secreted in two forms: inhibin-A and inhibin-B. Inhibin-B is secreted primarily in the follicular phase and is stimulated by FSH, whereas inhibin-A is mainly active in the luteal phase (89). Both forms of inhibin act to inhibit FSH synthesis and release (90,91). The second peptide, activin, stimulates FSH release from the pituitary gland and potentiates its action in the ovary (92,93). It is likely that there are numerous other intraovarian regulators similar to inhibin and activin, each of which may play a key role in promoting the normal ovulatory process (94). Some of these include follistatin, insulinlike growth factor-1 (ILGF-1), epidermal growth factor (EGF)/transforming growth factor-α (TGF-α), TGF-β1, fibroblast


Gynecology_Novak

Gynecology_Novak. the normal ovulatory process (94). Some of these include follistatin, insulinlike growth factor-1 (ILGF-1), epidermal growth factor (EGF)/transforming growth factor-α (TGF-α), TGF-β1, fibroblast growth factor-β (FGF-β), interleukin-1, tissue necrosis factor-α, OMI, and renin–angiotensin.


Gynecology_Novak

Gynecology_Novak. The midcycle LH surge is responsible for a dramatic increase in local concentrations of prostaglandins and proteolytic enzymes in the follicular wall (95). These substances progressively weaken the follicular wall and ultimately allow a perforation to form. Ovulation most likely represents a slow extrusion of the oocyte through this opening in the follicle rather than a rupture of the follicular structure (96). Direct measurements of intrafollicular pressures were recorded and failed to demonstrate an explosive event.


Gynecology_Novak

Gynecology_Novak. Luteal Phase Structure of Corpus Luteum After ovulation, the remaining follicular shell is transformed into the primary regulator of the luteal phase: the corpus luteum. Membranous granulosa cells remaining in the follicle begin to take up lipids and the characteristic yellow lutein pigment for which the structure is named. These cells are active secretory structures that produce progesterone, which supports the endometrium of the luteal phase. In addition, estrogen and inhibin-A are produced in significant quantities. Unlike the process that occurs in the developing follicle, the basement membrane of the corpus luteum degenerates to allow proliferating blood vessels to invade the granulosa-luteal cells in response to secretion of angiogenic factors such as vascular endothelial growth factor (97). This angiogenic response allows large amounts of luteal hormones to enter the systemic circulation.


Gynecology_Novak

Gynecology_Novak. Hormonal Function and Regulation The hormonal changes of the luteal phase are characterized by a series of negative feedback interactions designed to lead to regression of the corpus luteum if pregnancy does not occur. Corpus luteum steroids (estradiol and progesterone) provide negative central feedback and cause a decrease in FSH and LH secretion. Continued secretion of both steroids will decrease the stimuli for subsequent follicular recruitment. Similarly, luteal secretion of inhibin also potentiates FSH withdrawal. In the ovary, local production of progesterone inhibits the further development and recruitment of additional follicles.


Gynecology_Novak

Gynecology_Novak. Continued corpus luteum function depends on continued LH production. In the absence of this stimulation, the corpus luteum will invariably regress after 12 to 16 days and form the scarlike corpora albicans (98). The exact mechanism of luteolysis is unclear and most likely involves local paracrine factors. In the absence of pregnancy, the corpus luteum regresses, and estrogen and progesterone levels wane. This, in turn, removes central inhibition on gonadotropin secretion and allows FSH and LH levels to again rise and recruit another cohort of follicles.


Gynecology_Novak

Gynecology_Novak. If pregnancy does occur, placental hCG will mimic LH action and continually stimulate the corpus luteum to secrete progesterone. Successful implantation results in hormonal support to allow continued maintenance of the corpus luteum and the endometrium. Evidence from patients undergoing oocyte donation cycles demonstrated that continued luteal function is essential to continuation of the pregnancy until approximately 5 weeks of gestation, when sufficient progesterone is produced by the developing placenta (99). This switch in the source of regulatory progesterone production is referred to as the luteal–placental shift. Summary of Menstrual Cycle Regulation Following is a summary of the regulation of the menstrual cycle: 1. GnRH is produced in the arcuate nucleus of the hypothalamus and secreted in a pulsatile fashion into the portal circulation, where it travels to the anterior pituitary. 2.


Gynecology_Novak

Gynecology_Novak. GnRH is produced in the arcuate nucleus of the hypothalamus and secreted in a pulsatile fashion into the portal circulation, where it travels to the anterior pituitary. 2. Ovarian follicular development moves from a period of gonadotropin independence to a phase of FSH dependence. 3. As the corpus luteum of the previous cycle fades, luteal production of progesterone and inhibin-A decreases, allowing FSH levels to rise. 4. In response to FSH stimulus, the follicles grow, differentiate, and secrete increasing amounts of estrogen and inhibin-B. 5. Estrogen stimulates growth and differentiation of the functional layer of the endometrium, which prepares for implantation. Estrogens work with FSH in stimulating follicular development. 6. The two-cell, two-gonadotropin theory dictates that with LH stimulation, the ovarian theca cells will produce androgens that are converted by the granulosa cells into estrogens under the stimulus of FSH. 7.


Gynecology_Novak

Gynecology_Novak. 7. Rising estrogen and inhibin levels negatively feed back on the pituitary gland and hypothalamus and decrease the secretion of FSH. 8. The one follicle destined to ovulate each cycle is called the dominant follicle. It has relatively more FSH receptors and produces a larger concentration of estrogens than the follicles that will undergo atresia. It is able to continue to grow despite falling FSH levels. 9. Sustained high estrogen levels cause a surge in pituitary LH secretion that triggers ovulation, progesterone production, and the shift to the secretory, or luteal, phase. 10. Luteal function is dependent on the presence of LH. The corpus luteum secretes estrogen, progesterone, and inhibin-A, which serve to maintain gonadotropin suppression. Without continued LH secretion, the corpus luteum will regress after 12 to 16 days. The resulting loss of progesterone secretion results in menstruation. 11.


Gynecology_Novak

Gynecology_Novak. 11. If pregnancy occurs, the embryo secretes hCG, which mimics the action of LH by sustaining the corpus luteum. The corpus luteum continues to secrete progesterone and supports the secretory endometrium, allowing the pregnancy to continue to develop. 1. Bloom FE. Neuroendocrine mechanisms: cells and systems. In: Yen SCC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia, PA: Saunders, 1991:2–24. 2. Simerly RB, Chang C, Muramatsu M, et al. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 1990;294:76–95. 3. Brown TJ, Hochberg RB, Naftolin F. Pubertal development of estrogen receptors in the rat brain. Mol Cell Neurosci 1994;5:475–483. 4. Bergland RM, Page RB. Can the pituitary secrete directly to the brain? Affirmative anatomic evidence. Endocrinology 1978;102: 1325–1338. 5.


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Gynecology_Novak. 4. Bergland RM, Page RB. Can the pituitary secrete directly to the brain? Affirmative anatomic evidence. Endocrinology 1978;102: 1325–1338. 5. Duello TM, Halmi NS. Ultrastructural-immunocytochemical localization of growth hormone and prolactin in human pituitaries. J Clin Endocrinol Metab 1979;49:189–196. 6. Blackwell RE, Amoss M Jr, Vale W, et al. Concomitant release of FSH and LH induced by native and synthetic LRF. Am J Physiol 1973;224:170–175. 7. Krey LC, Butler WR, Knobil E. Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinology 1975;96:1073–1087. 8. Plant TM, Krey LC, Moossy J, et al. The arcuate nucleus and the control of the gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta). Endocrinology 1978;102:52–62. 9.


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Gynecology_Novak. Plant TM, Krey LC, Moossy J, et al. The arcuate nucleus and the control of the gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta). Endocrinology 1978;102:52–62. 9. Amoss M, Burgus R, Blackwell RE, et al. Purification, amino acid composition, and N-terminus of the hypothalamic luteinizing hormone releasing factor (LRF) of ovine origin. Biochem Biophys Res Commun 1971;44:205–210. 10. Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone releasing hormone neurons. Nature 1989;338:161–164. 11. Dierschke DJ, Bhattacharya AN, Atkinson LE, et al. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology 1970;87:850–853. 12. Knobil E. Neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 1980;36:53–88. 13. Belchetz PE, Plant TM, Nakai Y, et al. Hypophyseal responses to continuous and intermittent delivery of hypothalamic gonadotropinreleasing hormone. Science 1978;202:631–633. 14.


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Gynecology_Novak. 13. Belchetz PE, Plant TM, Nakai Y, et al. Hypophyseal responses to continuous and intermittent delivery of hypothalamic gonadotropinreleasing hormone. Science 1978;202:631–633. 14. Nakai Y, Plant TM, Hess DL, et al. On the sites of the negative and positive feedback actions of estradiol and the control of gonadotropin secretion in the rhesus monkey. Endocrinology 1978;102:1008–1014. 15. Rabin D, McNeil LW. Pituitary and gonadal desensitization after continuous luteinizing hormone–releasing hormone infusion in normal females. J Clin Endocrinol Metab1980,51:873–876. 16. Hoff JD, Lasley BL, Yen SSC. Functional relationship between priming and releasing actions of luteinizing hormone–releasing hormone. J Clin Endocrinol Metab 1979;49:8–11. 17. Soules MR, Steiner RA, Cohen NL, et al. Nocturnal slowing of pulsatile luteinizing hormone secretion in women during the follicu lar phase of the menstrual cycle. J Clin Endocrinol Metab 1985;61: 43–49. 18.


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Gynecology_Novak. 18. Filicori M, Santoro N, Marriam GR, et al. Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J Clin Endocrinol Metab 1986;62:1136– 1144. 19. Yu B, Ruman J, Christman G. The role of peripheral gonadotropinreleasing hormone receptors in female reproduction. Fertil Steril 2011;95:465–473. 20. Karten MJ, Rivier JE. Gonadotropin-releasing hormone analog design. Structure function studies towards the development of agonists and antagonists: rationale and perspective. Endocr Rev 1986;7: 44–66. 21. Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogs. Annu Rev Med 1994;45:391–405. 22. Loy RA. The pharmacology and potential applications of GnRH antagonists. Curr Opin Obstet Gynecol 1994;6:262–268. 23. Schally AV. LH-RH analogues. I. Their impact on reproductive medicine. Gynecol Endocrinol 1999;13:401–409. 24.


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Gynecology_Novak. 23. Schally AV. LH-RH analogues. I. Their impact on reproductive medicine. Gynecol Endocrinol 1999;13:401–409. 24. Halmos G, Schally AV, Pinski J, et al. Down-regulation of pituitary receptors for luteinizing hormone–releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix. Proc Natl Acad SciUSA 1996; 93:2398–2402. 25. Betz SF, Zhu YF, Chen C, Struthers RS. Non-peptide gonadotropinreleasing hormone receptor antagonists. J Med Chem 2008;51:3331– 3348. 26. Struthers RS, Nicholls AJ, Grundy J, et al. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab 2009;94:545–551. 27. Hughes J, Smith TW, Kosterlitz LH, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577–580. 28.


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Gynecology_Novak. 27. Hughes J, Smith TW, Kosterlitz LH, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577–580. 28. Howlett TA, Rees LH. Endogenous opioid peptide and hypothalamopituitary function. Annu Rev Physiol 1986;48:527–536. 29. Facchinetti F, Petraglia F, Genazzani AR. Localization and expression of the three opioid systems. Semin Reprod Endocrinol 1987;5: 103. 30. Goldstein A. Endorphins: physiology and clinical implications. Ann N Y Acad Sci 1978;311:49–58. 31. Grossman A. Opioid peptides and reproductive function. Semin Reprod Endocrinol 1987;5:115–124. 32. Reid Rl, Hoff JD, Yen SSC, et al. Effects of exogenous βendorphin on pituitary hormone secretion and its disappearance rate in normal human subjects. J Clin Endocrinol Metab 1981;52:1179– 1184. 33. Gindoff PR, Ferin M. Brain opioid peptides and menstrual cyclicity. Semin Reprod Endocrinol 1987;5:125–133. 34.


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Gynecology_Novak. 33. Gindoff PR, Ferin M. Brain opioid peptides and menstrual cyclicity. Semin Reprod Endocrinol 1987;5:125–133. 34. Halbreich U, Endicott J. Possible involvement of endorphin withdrawal or imbalance in specific premenstrual syndromes and postpartum depression. Med Hypotheses 1981;7:1045–1058. 35. Fiddes JC, Talmadge K. Structure, expression and evolution of the genes for human glycoprotein hormones. Recent Prog Horm Res 1984;40:43–78. 36. Vaitukaitis JL, Ross JT, Bourstein GD, et al. Gonadotropins and their subunits: basic and clinical studies. Recent Prog Horm Res 1976;32:289–331. 37. Lalloz MRA, Detta A, Clayton RN. GnRH desensitization preferentially inhibits expression of the LH β-subunit gene in vivo. Endocrinology 1988;122:1689–1694. 38. Brun del Re R, del Pozo E, de Grandi P, et al. Prolactin inhibition and suppression of puerperal lactation by a Br-ergocriptine (CB 154): a comparison with estrogen. Obstet Gynecol 1973;41:884–890. 39.


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Gynecology_Novak. 39. Suh HK, Frantz AG. Size heterogeneity of human prolactin in plasma and pituitary extracts. J Clin Endocrinol Metab 1974:39:928–935. 40. MacLeod RM. Inﬂuence of norepinephrine and catecholamine depletion agents synthesis in release of prolactin growth hormone. Endocrinology 1969;85:916–923. 41. Vale W, Blackwell RE, Grant G, et al. TRF and thyroid hormones on prolactin secretion by rat pituitary cell in vitro. Endocrinology 1973;93:26–33. 42. Matsushita N, Kato Y, Shimatsu A, et al. Effects of VIP, TRH, GABA and dopamine on prolactin release from superfused rat anterior pituitary cells. Life Sci 1983;32:1263–1269. 43. Dufy-Barbe L, Rodriguez F, Arsaut J, et al. Angiotensin-II stimulates prolactin release in the rhesus monkey. Neuroendocrinology 1982;35:242–247. 44. Burrow GN. The thyroid gland and reproduction. In: Yen SCC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia, PA: Saunders, 1991:555–575. 45.


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Gynecology_Novak. 44. Burrow GN. The thyroid gland and reproduction. In: Yen SCC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia, PA: Saunders, 1991:555–575. 45. Katz E, Ricciarelli E, Adashi EY. The potential relevance of growth hormone to female reproductive physiology and pathophysiology. Fertil Steril 1993;59:8–34. 46. Yen SCC. The hypothalamic control of pituitary hormone secretion. In: Yen SCC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia, PA: Saunders, 1991:65–104. 47. Insel TR. Oxytocin and the neuroendocrine basis of affiliation. In: Schulkin J, ed. Hormonally induced changes in mind and brain. New York: Academic Press, 1993:225–251. 48. Stein DJ. Oxytocin and vasopressin: social neuropeptides. CNS Spectr 2009;14:602–606. 49. Donaldson ZR, Young LJ. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008;322:900–904. 50.


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Gynecology_Novak. 49. Donaldson ZR, Young LJ. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008;322:900–904. 50. Yamasue H, Kuwabara H, Kawakubo Y, et al. Oxytocin, sexually dimorphic features of the social brain, and autism. Psychiatry Clin Neurosci 2009;63:129–140. 51. Israel S, Lerer E, Shalev I, et al. Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between. Prog Brain Res 2008;170:435–449. 52. McNeilly AS, Robinson IC, Houston MJ, et al. Release of oxytocin and PRL in response to suckling. BMJ 1983;286:257–259. 53. Dunn FL, Brennan TJ, Nelson AE, et al. The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest 1973;52:3212–3219. 54. Vollman RF. The menstrual cycle. In: Friedman E, ed. Major problems in obstetrics and gynecology. Philadelphia, PA: Saunders, 1977:1–193. 55.


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Gynecology_Novak. 54. Vollman RF. The menstrual cycle. In: Friedman E, ed. Major problems in obstetrics and gynecology. Philadelphia, PA: Saunders, 1977:1–193. 55. Treloar AE, Boynton RE, Borghild GB, et al. Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967;12:77–126. 56. Collett ME, Wertenberger GE, Fiske VM. The effects of age upon the pattern of the menstrual cycle. Fertil Steril 1954;5:437–448. 57. Noyes RW, Hertig AW, Rock J. Dating the endometrial biopsy. Fertil Steril 1950;1:3–25. 58. Flowers CE Jr, Wilbron WH. Cellular mechanisms for endometrial conservation during menstrual bleeding. Semin Reprod Endocrinol 1984;2:307–341. 59. Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 2004;70:1738– 1750. 60. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 2004;292:81–85. 61.


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Gynecology_Novak. 60. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 2004;292:81–85. 61. Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol 1979;133:859–867. 62. Schwarz BE. The production and biologic effects of uterine prostaglandins. Semin Reprod Endocrinol 1983;1:189. 63. Olive DL. The prevalence and epidemiology of luteal-phase deficiency in normal and infertile women. Clin Obstet Gynecol 1991;34:157– 166. 64. Murray MJ, Meyer WR, Zaino RJ, et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in infertile women. Fertil Steril 2004;81:1333–1343. 65. Coutifaris C, Myers ER, Guzick DS, et al. Histologic dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004;82:1264–1272. 66.


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Gynecology_Novak. 65. Coutifaris C, Myers ER, Guzick DS, et al. Histologic dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004;82:1264–1272. 66. Peters H, Byskov AG, Grinsted J. Follicular growth in fetal and prepubertal ovaries in humans and other primates. J Clin Endocrinol Metab 1978;7:469–485. 67. Himelstein-Braw R, Byskov AG, Peters H, et al. Follicular atresia in the infant human ovary. J Reprod Fertil 1976;46:55–59. 68. Wassarman PM, Albertini DF. The mammalian ovum. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press, 1994:240–244. 69. Johnson J, Canning J, Kaneko T, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004;428:145–150. 70. Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005;122:303–315. 71.


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Gynecology_Novak. 70. Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005;122:303–315. 71. Gondos B, Bhiraleus P, Hobel CJ. Ultrastructural observations on germ cells in human fetal ovaries. Am J Obstet Gynecol 1971;110:644– 652. 72. Tsafriri A, Dekel N, Bar-Ami S. A role of oocyte maturation inhibitor in follicular regulation of oocyte maturation. J Reprod Fertil 1982;64:541–551. 73. Halpin DMG, Jones A, Fink G, et al. Post-natal ovarian follicle development in hypogonadal (HPG) and normal mice and associated changes in the hypothalamic-pituitary axis. J Reprod Fertil 1986;77:287–296. 74. Vermesh M, Kletzky OA. Longitudinal evaluation of the luteal phase and its transition into the follicular phase. J Clin Endocrinol Metab 1987;65:653–658. 75.


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Gynecology_Novak. 74. Vermesh M, Kletzky OA. Longitudinal evaluation of the luteal phase and its transition into the follicular phase. J Clin Endocrinol Metab 1987;65:653–658. 75. Erickson GF, Magoffin DA, Dyer CA, et al. Ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 1985;6:371–399. 76. Erickson GF. An analysis of follicle development and ovum maturation. Semin Reprod Endocrinol 1986;46:55–59. 77. Ryan KJ, Petro Z. Steroid biosynthesis of human ovarian granulosa and thecal cells. J Clin Endocrinol Metab 1966;26:46–52. 78. Kobayashi M, Nakano R, Ooshima A. Immunohistochemical localization of pituitary gonadotropin and gonadal steroids confirms the two cells two gonadotropins hypothesis of steroidogenesis in the human ovary. J Endocrinol 1990;126:483–488. 79. Yamoto M, Shima K, Nakano R. Gonadotropin receptors in human ovarian follicles and corpora lutea throughout the menstrual cycle. Horm Res 1992;37[Suppl 1]:5–11. 80.


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Gynecology_Novak. 79. Yamoto M, Shima K, Nakano R. Gonadotropin receptors in human ovarian follicles and corpora lutea throughout the menstrual cycle. Horm Res 1992;37[Suppl 1]:5–11. 80. Hseuh AJ, Adashi EY, Jones PB, et al. Hormonal regulation of the differentiation of cultured ovarian granulosa cells. Endocr Rev 1984;5:76–127. 81. Weil SJ, Vendola K, Zhou J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998;83:2479–2485. 82. Chappel SC, Resko JA, Norman RL, et al. Studies on rhesus monkeys on the site where estrogen inhibits gonadotropins: delivery of 17 β-estradiol to the hypothalamus and pituitary gland. J Clin Endocrinol Metab 1981;52:1–8. 83. Chabab A, Hedon B, Arnal F, et al. Follicular steroids in relation to oocyte development in human ovarian stimulation protocols. Hum Reprod 1986;1:449–454. 84.


Gynecology_Novak

Gynecology_Novak. 83. Chabab A, Hedon B, Arnal F, et al. Follicular steroids in relation to oocyte development in human ovarian stimulation protocols. Hum Reprod 1986;1:449–454. 84. Young SR, Jaffe RB. Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women: II. Effects of varying concentrations of estradiol. J Clin Endocrinol Metab 1976;42:432–442. 85. Pauerstein CJ, Eddy CA, Croxatto HD, et al. Temporal relationship of estrogen, progesterone, luteinizing hormone levels to ovulation in women and infra-human primates. Am J Obstet Gynecol 1978;130: 876–886. 86. World Health Organization Task Force Investigators. Temporal relationship between ovulation and defined changes in the concentration of plasma estradiol-17β luteinizing hormone, follicle stimulating hormone and progesterone. Am J Obstet Gynecol 1980;138: 383. 87.


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Gynecology_Novak. 87. Hoff JD, Quigley NE, Yen SSC. Hormonal dynamics in mid-cycle: a re-evaluation. J Clin Endocrinol Metab 1983;57:792–796. 88. Demura R, Suzuki T, Tajima S, et al. Human plasma free activin and inhibin levels during the menstrual cycle. J Clin Endocrinol Metab 1993;76:1080–1082. 89. Groome NP, Illingworth PG, O’Brien M, et al. Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 1996;81:1401–1405. 90. McLachlan RI, Robertson DM, Healy DL, et al. Circulating immunoreactive inhibin levels during the normal human menstrual cycle. J Clin Endocrinol Metab 1987;65:954–961. 91. Buckler HM, Healy DL, Burger HG. Purified FSH stimulates inhibin production from the human ovary. J Endocrinol 1989;122:279–285. 92. Ling N, Ying S, Ueno N, et al. Pituitary FSH is released by het erodimer of the β-subunits from the two forms of inhibin. Nature 1986; 321:779–782. 93.


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Gynecology_Novak. 92. Ling N, Ying S, Ueno N, et al. Pituitary FSH is released by het erodimer of the β-subunits from the two forms of inhibin. Nature 1986; 321:779–782. 93. Braden TD, Conn PM. Activin-A stimulates the synthesis of gonadotropin-releasing hormone receptors. Endocrinology 1992;130: 2101–2105. 94. Adashi EY. Putative intraovarian regulators. Semin Reprod Endocrinol 1988;7:1–100. 95. Yoshimura Y, Santulli R, Atlas SJ, et al. The effects of proteolytic enzymes on in vitro ovulation in the rabbit. Am J Obstet Gynecol 1987;157:468–475. 96. Yoshimura Y, Wallach EE. Studies on the mechanism(s) of mammalian ovulation. Fertil Steril 1987;47:22–34. 97. Anasti JN, Kalantaridou SN, Kimzey LM, et al. Human follicle ﬂuid vascular endothelial growth factor concentrations are correlated with luteinization in spontaneously developing follicles. Hum Reprod 1998;13:1144–1147. 98.


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Gynecology_Novak. 98. Lenton EA, Landgren B, Sexton L. Normal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase. Br J Obstet Gynaecol 1994;91:685. 99. Scott R, Navot D, Hung-Ching L, et al. A human in vivo model for the luteal placental shift. Fertil Steril 1991;56:481–484. Paula J. Adams Hillard Preventive health services that encompass screening and counseling for a broad range of health behaviors and risks are important components of general obstetric and gynecologic care. Traditional gynecologic care—including cervical cytology testing, pelvic and breast screening examinations, and the provision of contraceptive services—is considered primary preventive care.


Gynecology_Novak

Gynecology_Novak. Traditional gynecologic care—including cervical cytology testing, pelvic and breast screening examinations, and the provision of contraceptive services—is considered primary preventive care. Routine health care assessments for healthy women include a medical history, physical examination, routine and indicated laboratory studies, assessment and counseling regarding healthy behaviors, and relevant interventions, taking into account the leading causes of morbidity and mortality within different age groups. Evidence-based guidelines for the provision of periodic health evaluations, screening, and counseling have been developed by the American College of Obstetricians and Gynecologists (ACOG) and other organizations; these guidelines provide the basis for routine preventive health assessment and screening recommendations.


Gynecology_Novak

Gynecology_Novak. Preventive services for adolescents should be based on knowledge of the behavioral and medical health risks that place their future health at risk, including substance use and abuse, sexual behaviors that increase the risks of unintended pregnancy and sexually transmitted diseases (STDs), and impaired mental health. Obesity, smoking, and alcohol abuse are preventable problems that have a major impact on long-term health; assessment, counseling, and referral for these health risks is a component of periodic health assessment and primary care.


Gynecology_Novak

Gynecology_Novak. Although obstetricians-gynecologists have focused on the management of abnormal gynecologic conditions, they also have a traditional role of providing primary and preventive care to women, particularly for women of reproductive age. The obstetrician-gynecologist often serves as a woman’s point of entry into the health care system, her primary care clinician, and a source of continuity of care (1). Primary care emphasizes health maintenance, preventive services, early detection of disease, and availability and continuity of care. The value of preventive services is apparent in such trends as the reduced mortality rate from cervical cancer that resulted, in large part, from the increased use of cervical cytology testing. Neonatal screening for phenylketonuria (PKU) and hypothyroidism are examples of effective mechanisms for prevention of mental retardation. Women often regard their gynecologist as their primary care provider; indeed, many women of reproductive age have no other


Gynecology_Novak

Gynecology_Novak. are examples of effective mechanisms for prevention of mental retardation. Women often regard their gynecologist as their primary care provider; indeed, many women of reproductive age have no other physician. Obstetricians-gynecologists estimated that at least a third of their nonpregnant patients rely on them for primary care (2). As primary care physicians, obstetricians-gynecologists provide ongoing care for women through all stages of their lives—from reproductive age to postmenopause. In this role, some gynecologists include as a routine part of their practices screening for certain medical conditions, such as hypertension, diabetes mellitus, and thyroid disease, and management of those conditions in the absence of complications.


Gynecology_Novak

Gynecology_Novak. Some traditional aspects of gynecologic practice, such as family planning and preconception counseling, are recognized as effective preventive health measures, although clear and coherent national guidelines and goals for preventing unintended pregnancies have not been a high priority in the United States (3). Preventive medical services encompass screening and counseling for a broad range of health behaviors and risks, including sexual practices; prevention of sexually transmitted diseases (STDs); use of tobacco, alcohol, and other drugs; diet; and exercise.


Gynecology_Novak

Gynecology_Novak. The Institute of Medicine defined primary care as “the provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients, and practicing in the context of family and community” (4). Integrated care is further defined as being comprehensive, coordinated, and continuous. The definition states that primary care clinicians have the appropriate training to manage most problems that afﬂict patients (including physical, mental, emotional, and social concerns) and to involve other practitioners for further evaluation or treatment when appropriate. Using data from the National Ambulatory Medical Care Surveys, physician specialty groups were analyzed in a study to determine how well these Institute of Medicine primary care definitions applied to the care delivered by each specialty (5). In this analysis, obstetrics and gynecology as a specialty demonstrated


Gynecology_Novak

Gynecology_Novak. to determine how well these Institute of Medicine primary care definitions applied to the care delivered by each specialty (5). In this analysis, obstetrics and gynecology as a specialty demonstrated some characteristics of primary care that applied to the traditional specialties of internal medicine, family and general physicians, and pediatrics. As a category, however, obstetrics and gynecology was more closely related to medical and surgical subspecialties (5). This analysis would be accepted by many practicing obstetricians and gynecologists who state that the specialty provides both primary and specialty care.


Gynecology_Novak

Gynecology_Novak. The Institute of Medicine definition includes referral, coordination, and follow-up care, but specifically does not include the function of “gatekeeper” as essential for a primary care clinician. As the US health care system has evolved, health maintenance organizations and insurers have responded to women’s resolute support of direct access to obstetricians-gynecologists, a concept also strongly supported by the American Congress of Obstetricians and Gynecologists (6). There is an increasing emphasis on women’s health and gender-specific medicine. Physicians have become more knowledgeable about the differences in pathophysiologic aspects of diseases in women compared with men and thus better equipped to manage them. One example is an increasing emphasis on women’s cardiovascular health with preventive care and screening for risk factors. Gynecologist as Primary Care Provider


Gynecology_Novak

Gynecology_Novak. The obstetrician-gynecologist frequently serves as a primary medical resource for women and their families, providing information, guidance, and referrals when appropriate. Routine health care assessments for healthy women are based on age groups and risk factors. Health guidance takes into account the leading causes of morbidity and mortality within different age groups. Patient counseling and education require an ability to assess individual needs, to assess stages of readiness for change, and to use good communication skills, including motivational interviewing to encourage behavioral changes and ongoing care (7). A team approach to care is frequently helpful, utilizing the expertise of medical colleagues, such as nurses; advanced practice nurses, including nurse midwives and nurse practitioners; health educators; other allied health professionals, such as dieticians or physical therapists; relevant social services; and other physician specialists. All clinicians, regardless of the


Gynecology_Novak

Gynecology_Novak. health educators; other allied health professionals, such as dieticians or physical therapists; relevant social services; and other physician specialists. All clinicians, regardless of the extent of their training, have limitations to their knowledge and skills and should seek consultation at appropriate times for the benefit of their patients in providing both reproductive and nonreproductive care.


Gynecology_Novak

Gynecology_Novak. The National Ambulatory Care Surveys from the Centers for Disease Control and Prevention include obstetrician-gynecologists among primary care specialties as opposed to medical or surgical subspecialties (8). Women’s needs for primary care vary across their lifespan. One survey of women’s satisfaction with primary care found that women in their early reproductive years (ages 18–34) were more satisfied with care coordination and comprehensiveness when their regular provider was a reproductive health specialist, primarily an obstetrician-gynecologist physician as compared to a generalist, a generalist clinician plus an obstetrician-gynecologist, or no regular provider (9). The scope of services provided by obstetricians-gynecologists varies from one practice or clinician to another and may include more or fewer aspects of well-woman and reproductive health care. It is important to establish with each patient whether she has a primary care clinician and who will be providing primary care


Gynecology_Novak

Gynecology_Novak. more or fewer aspects of well-woman and reproductive health care. It is important to establish with each patient whether she has a primary care clinician and who will be providing primary care and preventive health services (1).


Gynecology_Novak

Gynecology_Novak. Guidelines for primary and preventive services are issued by a number of medical bodies including the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians, the U.S. Preventive Services Task Force (USPSTF), and the American Medical Association (1,10–14). The guidelines from various organizations differ somewhat in their specific details, and a national guideline clearinghouse for evidence-based clinical practice guidelines, sponsored by the Agency for Healthcare Research and Quality (AHRQ), is available to provide comparisons between guidelines for a given medical condition or intervention (15).


Gynecology_Novak

Gynecology_Novak. In 2006 in the United States, there were approximately 660 million visits by women to ambulatory medical care providers (16). In the past, approximately eighteen percent of the visits were made to gynecologists (17). Less than a third of ambulatory visits were made by individuals between the ages of 15 and 44 years, and this percentage is declining with an aging population (16). Normal pregnancy and gynecologic examination were among the most common reasons for care.


Gynecology_Novak

Gynecology_Novak. Normal pregnancy and gynecologic examination were among the most common reasons for care. When asked to characterize the nature of an office or clinic visit, obstetricians-gynecologists may or may not identify themselves as primary care providers, depending on a number of variables (18). Those variables may include the patient’s age, pregnancy status, whether it is a new versus a return visit, the diagnosis, insurance or referral status, and even geographic practice region. Primary and preventive services clearly within the realm of obstetricians and gynecologists include cervical cytology testing, pelvic examination and breast examination, and family planning services including contraception. When compared with other physicians, obstetricians-gynecologists are more likely than other physicians to perform cervical cytology testing, pelvic examination, and breast examination. Approaches to Preventive Care


Gynecology_Novak

Gynecology_Novak. Approaches to Preventive Care In health care, the focus is shifting from disease to prevention. Efforts are under way to promote effective screening measures that can have a beneficial effect on public and individual health. Following is a brief description of programs developed by American College of Obstetricians and Gynecologists (ACOG), the USPSTF, and the American Medical Association to provide guidelines for preventive care.


Gynecology_Novak

Gynecology_Novak. The initial evaluation of a patient involves a complete history, physical examination, routine and indicated laboratory studies, evaluation and counseling, appropriate immunizations, and relevant interventions. Risk factors should be identified and arrangements should be made for continuing care or referral, as needed. The ACOG recommendations for periodic evaluation, screening, and counseling by age groups, and the leading causes of death and morbidity within different age groups are shown in Tables 8.1 through 8.4 (10). These tables include recommendations for patients who have high-risk factors that require targeted screening or treatment; patients should be made aware of any high-risk conditions that require more specific screening or treatment (Table 8.5). Recommendations for immunizations, indicated according to age group, are available from the U.S. Centers for Disease Control and Prevention (CDC). The CDC recommends HIV screening for pregnant women, adults, and adolescent


Gynecology_Novak

Gynecology_Novak. indicated according to age group, are available from the U.S. Centers for Disease Control and Prevention (CDC). The CDC recommends HIV screening for pregnant women, adults, and adolescent patients in all health care settings after the patient is notified that testing will be performed, unless the patient declines (opt-out screening) (19). Subsequent care should follow a specific schedule, yearly or as appropriate, based on the patient’s needs and age.


Gynecology_Novak

Gynecology_Novak. Table 8.1 Periodic Assessment Ages 13–18 Years Health status: medical, menstrual, surgical, family High-risk behaviors Use of complementary and alternative medicine —Contraceptive options, including emergency contraception Tobacco, alcohol, other drug use Sexually transmitted diseases Height Exercise: discussion of program Pelvic examination (when indicated by the Suicide: depressive symptoms medical history) Hygiene (including dental), ﬂuoride supplementation* Table 8.1 (Continued ) Skin exposure to ultraviolet rays Leading Causes of Death¶ Tobacco, alcohol, other drug use 1. Accidents (unintentional injuries) Immunizations 2. Malignant neoplasms Periodic 3. Intentional self harm (suicide) Diphtheria and reduced tetanus toxoids and 4. Assault (homicide) acellular pertussis vaccine booster (once between ages 11–18 years)|| Hepatitis B vaccine (one series for those not 5. Diseases of the heart previously immunized)


Gynecology_Novak

Gynecology_Novak. Hepatitis B vaccine (one series for those not 5. Diseases of the heart previously immunized) Human papillomavirus vaccine (one series for 6. Congenital malformations, deformations, and chromosomal those not previously immunized, ages 9–26 abnormalities years) Inﬂuenza vaccine (annually) 7. Chronic lower respiratory diseases Measles–mumps–rubella vaccine (for those not 8. Cerebrovascular diseases previously immunized) *See Table 8.5. †Urine-based sexually transmitted disease screening is an efficient means for accomplishing such screening without a speculum examination.


Gynecology_Novak

Gynecology_Novak. ‡Physicians should be aware of and follow their states’ HIV screening requirements. For a more detailed discussion of HIV screening, see Branson BM, Handsfield HH, Lampe MA, Janssen RS, Taylor AW, Lyss SB, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep 2006;55(RR-14):1–17; quiz CE1–4. See also Routine human immunodeficiency virus screening. ACOG Committee Opinion No. 411. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008;112:401–3. §Only for those with a family history of familial adenomatous polyposis or 8 years after the start of pancolitis. For a more detailed discussion of colorectal cancer screening, see Levin B, Lieberman DA. McFarland B, Smith RA, Brooks D, Andrews KS, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer


Gynecology_Novak

Gynecology_Novak. McFarland B, Smith RA, Brooks D, Andrews KS, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. CA Cancer J Clin 2008;58:130–60. ||For more information on the use of Td and Tdap, see Broder KR, Cortese MM, Iskander JK, Kretsinger K, Slade BA, Brown KH, et al. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-3):1–34. ¶Leading causes of mortality are provided by the Mortality Statistics Branch at the


Gynecology_Novak

Gynecology_Novak. Practices (ACIP). Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-3):1–34. ¶Leading causes of mortality are provided by the Mortality Statistics Branch at the National Center for Health Statistics. Data are from 2004, the most recent year for which final data are available. The causes are ranked. From American College of Obstetricians and Gynecologists. Primary and preventive care: periodic assessments. ACOG Committee Opinion No. 452. Obstet Gynecol 2009;144:1444–1451.


Gynecology_Novak

Guide to Clinical Preventive Services

Gynecology_Novak. Guide to Clinical Preventive Services


Gynecology_Novak

Gynecology_Novak. The USPSTF was commissioned in 1984 as a 20-member nongovernmental panel of experts in primary care medicine, epidemiology, and public health. The USPSTF, comprising primary care providers, now includes nonfederal experts in prevention and evidence-based medicine (such as internists, pediatricians, family physicians, gynecologists-obstetricians, nurses, and health behavior specialists); the task force conducts and publishes scientific evidence reviews on a variety of preventive health services with administrative and research support from the AHRQ. Initial and subsequent reviews and recommendations are being revised and periodically released on the Web site sponsored by the AHRQ (15). The charge to the panel was to develop recommendations for the appropriate use of preventive interventions based on a systematic review of evidence of clinical effectiveness. The panel was asked to rigorously evaluate clinical research to assess the merits of preventive measures, including screening


Gynecology_Novak

Gynecology_Novak. based on a systematic review of evidence of clinical effectiveness. The panel was asked to rigorously evaluate clinical research to assess the merits of preventive measures, including screening tests, counseling, immunizations, and medications.


Gynecology_Novak

Gynecology_Novak. Table 8.2 Periodic Assessment Ages 19–39 Years Health status: medical, surgical, family Tuberculosis skin testing Use of complementary and alternative medicine Contraceptive options for prevention of unwanted pregnancy, including emergency contraception Tobacco, alcohol, other drug use Discussion of a reproductive health plan§ Blood pressure Exercise: discussion of program Neck: adenopathy, thyroid Dietary/nutrition assessment Pelvic examination: for ages 19–20 years, when indicated by the Psychosocial Evaluation medical history; age 21 or older, periodic pelvic examination Cervical cytology†: Work satisfaction Age 21 years: screen every 2 years Lifestyle/stress Age 30 years or older: Sleep disorders


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Gynecology_Novak. Cervical cytology†: Work satisfaction Age 21 years: screen every 2 years Lifestyle/stress Age 30 years or older: Sleep disorders Option 1: may screen every 3 years after three consecutive Cardiovascular Risk Factors negative test results with no history of cervical intraepithelial neoplasia 2 or 3, immunosuppression, human immunodeficiency virus (HIV) infection, or diethylstilbestrol exposure in utero; or Option 2: screen every 3 years after negative human Family history papillomavirus DNA test and negative cervical cytology Table 8.2 (Continued ) —Safety belts and helmets Leading Causes of Death** Skin exposure to ultraviolet rays 1. Malignant neoplasms Suicide: depressive symptoms 2. Accidents (unintentional injuries) Tobacco, alcohol, other drug use 3. Diseases of the heart Immunizations 4. Intentional self harm (suicide) Periodic 5. Human immunodeficiency virus (HIV) disease


Gynecology_Novak

Gynecology_Novak. Tobacco, alcohol, other drug use 3. Diseases of the heart Immunizations 4. Intentional self harm (suicide) Periodic 5. Human immunodeficiency virus (HIV) disease Diphtheria and reduced tetanus toxoids and acellular 6. Assault (homicide) pertussis vaccine (substitute one-time dose of Tdap for Td booster; then boost with Td every 10 years)# Human papillomavirus vaccine (one series for those aged 7. Cerebrovascular diseases 26 years or less and not previously immunized) Varicella vaccine (one series for those without evidence of 8. Diabetes mellitus immunity) High-Risk Groups* 9. Chronic liver diseases and cirrhosis Hepatitis A vaccine (consider combination vaccine for those 10. Chronic lower respiratory diseases at risk far hepatitis A and B) *See Table 8.5.


Gynecology_Novak

Gynecology_Novak. Hepatitis A vaccine (consider combination vaccine for those 10. Chronic lower respiratory diseases at risk far hepatitis A and B) *See Table 8.5. †For a more detailed discussion of cervical cytology screening, including the use of human papillomavirus DNA testing and screening after hysterectomy, see Cervical cytology screening. ACOG Practice Bulletin No. 109. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009:114: 1409–20.


Gynecology_Novak

Gynecology_Novak. ‡Physicians should be aware of and follow their states’ HIV screening requirements. For a more detailed discussion of HIV screening, see Branson BM, Handsfield HH, Lampe MA, Janssen RS, Taylor AW, Lyss SB, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep 2006;55(RR-14):1–17; quiz CE1–4. See also Routine human immunodeficiency virus screening. ACOG Committee Opinion No. 411. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008;112:401–3. §For a more detailed discussion of the reproductive health plain, see The importance of preconception care in the continuum of women’s health care. ACOG Committee Opinion No. 313. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005;106:665–6. ||Despite a lack of definitive data for or against breast self-examination, breast self-examination has the potential to detect palpable


Gynecology_Novak

Gynecology_Novak. and Gynecologists. Obstet Gynecol 2005;106:665–6. ||Despite a lack of definitive data for or against breast self-examination, breast self-examination has the potential to detect palpable breast cancer and can be recommended. ¶For a more detailed discussion of risk assessment and chemoprevention therapy, see Selective estrogen receptor modulators. ACOG Practice Bulletin No. 39. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:835–43. #For more information on the use of Td and Tdap, see Kretsinger K, Broder KR, Cortese MM, Joyce MP, Ortega-Sanchez I, Lee GM, et al. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. Centers for Disease Control


Gynecology_Novak

Gynecology_Novak. (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices; Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 2006;55(RR-17):1–37. **Leading causes of mortality are provided by the Mortality Statistics Branch at the National Center for Health Statistics. Data are from 2004, the most recent year for which final data are available. The causes are ranked. From American College of Obstetricians and Gynecologists, Primary and preventive care: periodic assessments. ACOG Committee Opinion No. 452. Obstet Gynecol 2009;144:1444–1451.


Gynecology_Novak

Gynecology_Novak. The task force uses systematic reviews of the evidence on specific topics in clinical prevention that serve as the scientific basis for recommendations. The task force reviews the evidence, estimates the magnitude of benefits and harms, reaches consensus about the net benefit of a given preventive service, and issues a recommendation that is assigned a grade from “A” (strongly recommends), to “B” (recommends), “C” (no recommendations for or against), “D” (recommends against), to “I” (insufficient evidence to recommend for or against) (Table 8.6). The grading system includes suggestions for practice, recommending that the service should be provided, discouraged, or that the uncertainty about the balance of benefits versus harms should be discussed. The levels of certainty regarding net benefit are ranked from high to moderate to low. The task force evaluates services based on age, gender, and risk factors for disease, making recommendations about which preventive services should be


Gynecology_Novak

Gynecology_Novak. benefit are ranked from high to moderate to low. The task force evaluates services based on age, gender, and risk factors for disease, making recommendations about which preventive services should be included in


Gynecology_Novak

Gynecology_Novak. Table 8.3 Periodic Assessment Ages 40–64 Years Health status: medical, surgical, family Contraceptive options for prevention of unwanted pregnancy, including emergency contraception Use of complementary and alternative medicine —Partner selection Tobacco, alcohol, other drug use —Barrier protection Menopausal symptoms Exercise: discussion of program Neck: adenopathy, thyroid Sleep disorders Breasts, axillae Cardiovascular Risk Factors Cervical cytology (may screen every 3 years after three consecutive Lifestyle negative test results if no history of cervical intraepithelial neoplasia 2 or 3, immunosuppression, human immunodeficiency virus infection (HIV), or diethylstilbestrol exposure in utero, or every 3 years after negative human papillomavirus DNA test and negative cervical cytology† Colorectal cancer screening (beginning at age 50 years∗: Health/Risk Behaviors colonoscopy every 10 years [preferred])


Gynecology_Novak

Gynecology_Novak. Colorectal cancer screening (beginning at age 50 years∗: Health/Risk Behaviors colonoscopy every 10 years [preferred]) Fasting glucose testing (every 3 years after age 45 years) Aspirin prophylaxis to reduce the risk of stroke (ages 55–79 years)¶ Mammography (every 1–2 years beginning at age 40 years, yearly Hormone therapy beginning at age 50 years) Sexually transmitted disease testing Skin exposure to ultraviolet rays Thyroid-stimulating hormone testing Suicide: depressive symptoms Tuberculosis skin testing Tobacco, alcohol, other drug use Table 8.3 (Continued ) Immunizations Leading Causes of Death‡‡ Periodic 1. Malignant neoplasms Diphtheria and reduced tetanus toxoids and acellular pertussis 2. Diseases of the heart vaccine booster (substitute one-time dose of Tdap for Td booster; then boost with Td every 10 years)†† Herpes zoster (single dose in adults aged 60 years or older) 3. Accidents (unintentional injuries)


Gynecology_Novak

Gynecology_Novak. Herpes zoster (single dose in adults aged 60 years or older) 3. Accidents (unintentional injuries) Inﬂuenza vaccine (annually beginning at age 50 years) 4. Chronic lower respiratory diseases Varicella vaccine (one series for those without evidence of 5. Cerebrovascular diseases immunity) High-Risk Groups* 6. Diabetes mellitus Hepatitis A vaccine (consider combination vaccine for those at 7. Chronic liver disease and cirrhosis risk for hepatitis A and B) Hepatitis B vaccine (consider combination vaccine for those at 8. Septicemia risk for hepatitis A and B) Inﬂuenza vaccine 9. Intentional self harm (suicide) Measles–mumps–rubella vaccine 10. Human immunodeficiency virus (HIV) disease ∗See Table 8.5.


Gynecology_Novak

Gynecology_Novak. Inﬂuenza vaccine 9. Intentional self harm (suicide) Measles–mumps–rubella vaccine 10. Human immunodeficiency virus (HIV) disease ∗See Table 8.5. a more detailed discussion of cervical cytology screening, including the use of human papillomavirus DNA testing and screening after hysterectomy, see Cervical cytology screening. ACOG Practice Bulletin No. 109. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009:114: 1409–20.


Gynecology_Novak

Gynecology_Novak. methods include: 1) fecal occult blood testing or fecal immunochemical test, annual patient-collected (fecal occult blood testing and fecal immunochemical testing require two or three samples of stool collected by the patient at home and returned for analysis. A single stool sample obtained by digital rectal examination is not adequate for the detection of colorectal cancer); 2) ﬂexible sigmoidoscopy every 5 years; 3) double contrast barium enema every 5 years; 4) computed tomography colonography every 5 years; and 5) stool DNA. The American College of Gastroenterology recommends that African Americans begin screening at age 45 years with colonoscopy because of increased incidence and earlier age of onset of colorectal cancer. (Agrawal S, Bhupinderjit A, Bhutani MS, Boardman L, Nguyen C, Romero Y, et al. Colorectal cancer in African Americans. Committee of Minority Affairs and Cultural Diversity, American College of Gastroenterology [published erratum appears in Am J Gastroenterol


Gynecology_Novak

Gynecology_Novak. C, Romero Y, et al. Colorectal cancer in African Americans. Committee of Minority Affairs and Cultural Diversity, American College of Gastroenterology [published erratum appears in Am J Gastroenterol 2005;100:1432]. Am J Gastroenterol 2005;100:515, 523; discussion 514.) §Physicians should be aware of and follow their states’ HIV screening requirements. For a more detailed discussion of HIV screening, see Branson BM, Handsfield HH, Lampe MA, Janssen RS, Taylor AW, Lyss SB, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep 2006;55(RR-14):1–17; quiz CE1–4. See also Routine human immunodeficiency virus screening. ACOG Committee Opinion No. 411. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008;112:401–3. ||Preconception and genetic counseling is appropriate for certain women in this age group. ¶The recommendation for aspirin prophylaxis


Gynecology_Novak

Gynecology_Novak. Obstetricians and Gynecologists. Obstet Gynecol 2008;112:401–3. ||Preconception and genetic counseling is appropriate for certain women in this age group. ¶The recommendation for aspirin prophylaxis must weigh the benefits of stroke prevention against the harm of gastrointestinal bleeding. See Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. U.S. Preventive Services Task Force. Ann Intern Med 2009;150:396–404. #Despite a lack of definitive data for or against breast self-examination, breast self-examination has the potential to detect palpable breast cancer and can be recommended. ∗∗For a more detailed discussion of risk assessment and chemoprevention therapy, see Selective estrogen receptor modulators. ACOG Practice Bulletin No. 39. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:835–43.


Gynecology_Novak

Gynecology_Novak. Tdap not previously given, give one time, then Td every 10 years thereafter. If Tdap previously given, give Td every 10 years. For more information on the use of Td and Tdap, see Kretsinger K, Broder KR, Cortese MM, Joyce MP, Ortega-Sanchez I, Lee GM, et al. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the Advisory Committeeon Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices; Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 2006;55(RR-17):1–37.


Gynecology_Novak

Gynecology_Novak. causes of mortality are provided by the Mortality Statistics Branch at the National Center for Health Statistics. Data are from 2004, the most recent year for which final data are available. The causes are ranked. From American College of Obstetricians and Gynecologists, Primary and preventive care: periodic assessments. ACOG Committee Opinion No. 452. Obstet Gynecol 2009;144:1444–1451.


Gynecology_Novak

Gynecology_Novak. routine primary care for which populations. Primary preventive measures are those that involve intervention before the disease develops, for example, quitting smoking, increasing physical activity, eating a healthy diet, quitting alcohol and other drug use, using seat belts, and receiving immunizations. Secondary preventive measures are those used to identify and treat asymptomatic persons who have risk factors or preclinical disease but in whom the disease itself has not become clinically apparent. Examples of secondary preventive measures are well known in gynecology, such as screening mammography and cervical cytology testing. Table 8.4 Periodic Assessment Ages 65 and Older Health status: medical, surgical, family Human immunodeficiency virus (HIV) testing Use of complementary and alternative medicine Sexuality Tobacco, alcohol, other drjg use, and concurrent medication use Sexual function Weight Exercise: discussion of program Neck: adenopathy, thyroid Neglect/abuse


Gynecology_Novak

Gynecology_Novak. Tobacco, alcohol, other drjg use, and concurrent medication use Sexual function Weight Exercise: discussion of program Neck: adenopathy, thyroid Neglect/abuse Breasts, axillae Lifestyle/stress Bone mineral density screening (In the absence of new risk Dyslipidemia factors, screen no more frequently than every 2 years.)


Gynecology_Novak

Gynecology_Novak. Breasts, axillae Lifestyle/stress Bone mineral density screening (In the absence of new risk Dyslipidemia factors, screen no more frequently than every 2 years.) Cervical cytology: consider discontinuing at age 65 years or Obesity 70 years if patient has had three or more normal results in a row, no abnormal results in 10 years, no history of cervical cancer, no history of diethylstilbestrol exposure in utero, is human immunodeficiency virus (HIV) negative, is not immunosuppressed; if cervical cytology has been discontinued, annual review of risk factors to evaluate need for reinitiation of screening. If cervical cytology is needed: may screen every 3 years after three consecutive negative test results if no history of cervical intraepithelial neoplasia 2 or 3, immunosuppression, HIV infection, or diethylstilbestrol exposure in utero or every 3 years after negative human papillomavirus DNA test and negative cervical cytology.‡


Gynecology_Novak

Gynecology_Novak. Colorectal cancer screening§: colonoscopy every 10 years Diabetes mellitus (preferred) Table 8.4 (Continued ) —Exercise and sports involvement Leading Causes of Death∗∗ —Firearms 1. Diseases of the heart —Occupational hazards 2. Malignant neoplasms —Prevention of falls 3. Cerebrovascular diseases —Recreational hazards 4. Chronic lower respiratory diseases —Safety belts and helmets 5. Alzheimer’s disease Skin exposure to ultraviolet rays 6. Inﬂuenza and pneumonia Suicide: depressive symptoms 7. Diabetes mellitus Tobacco, alcohol, other drug use 8. Nephritis, nephrotic syndrome, and nephrosis Visual acuity/glaucoma 9. Accidents (unintentional injuries) Immunizations 10. Septicemia Herpes zoster (single dose, if not previously immunized)


Gynecology_Novak

Gynecology_Novak. Visual acuity/glaucoma 9. Accidents (unintentional injuries) Immunizations 10. Septicemia Herpes zoster (single dose, if not previously immunized) Varicella vaccine (one series for those without evidence of immunity) ∗When a woman’s age or other health issues are such that she would not choose to intervene on conditions detected during the routine examination, it is reasonable to discontinue pelvic exams. †See Table 8.5.


Gynecology_Novak

Gynecology_Novak. ‡For a more detailed discussion of cervical cytology screening, including the use of human papillomavirus DNA testing and screening after hysterectomy, see Cervical cytology screening. ACOG Practice Bulletin No. 109. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009:114; 1409–20. §Other methods include: 1) fecal occult blood testing or fecal immunochemical test, annual patient-collected (fecal occult blood testing and fecal immunochemical testing require two or three samples of stool collected by the patient at home and returned for analysis. A single stool sample obtained by digital rectal examination is not adequate for the detection of colorectal cancer); 2) ﬂexible sigmoidoscopy every 5 years; 3) double contrast barium enema every 5 years; 4) computed tomography colonography every 5 years; and 5) stool DNA. More frequent testing is recommended for those with other risk factors. ||The recommendation for aspirin prophylaxis must weigh the benefits of stroke


Gynecology_Novak

Gynecology_Novak. colonography every 5 years; and 5) stool DNA. More frequent testing is recommended for those with other risk factors. ||The recommendation for aspirin prophylaxis must weigh the benefits of stroke prevention against the harm of gastrointestinal bleeding. See Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. U.S. Preventive Services Task Force. Ann Intern Med 2009;150:396–404. ¶Despite a lack of definitive data for or against breast self-examination, breast self-examination has the potential to detect palpable breast cancer and can be recommended. #For a more detailed discussion of risk assessment and chemoprevention therapy, see Selective estrogen receptor modulators. ACOG Practice Bulletin No. 39. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:835–43. ∗∗Leading causes of mortality are provided by the Mortality Statistics Branch at the National Center for Health Statistics. Data are from


Gynecology_Novak

Gynecology_Novak. and Gynecologists. Obstet Gynecol 2002;100:835–43. ∗∗Leading causes of mortality are provided by the Mortality Statistics Branch at the National Center for Health Statistics. Data are from 2004, the most recent year for which final data are available. The causes are ranked. From American College of Obstetricians and Gynecologists, Primary and preventive care: periodic assessments. ACOG Committee Opinion No. 452. Obstet Gynecol 2009;144:1444–1451.


Gynecology_Novak

Gynecology_Novak. The USPSTF is supported by an Evidence-Based Practice Center (EPC), which conducts systematic reviews of the evidence that serve as the scientific basis for USPSTF recommendations. These reviews analyze the effectiveness of various screening measures and tests. Preventive medicine and the discipline of evidence-based medicine have grown and evolved since the release of the first Guide to Clinical and Preventive Services in 1989. This document accelerated the trend to replace consensus or expert opinion in clinical recommendations with a more systematic and explicit review of the evidence. The USPSTF has recognized that scientific evidence, including evidence derived from a variety of research designs other than randomized clinical trials, does Table 8.5 High-Risk Factors


Gynecology_Novak

Gynecology_Novak. Table 8.5 High-Risk Factors Bone mineral density screening∗ Postmenopausal women younger than age 65 years: history of prior fracture as an adult; family history of osteoporosis; Caucasian; dementia; poor nutrition; smoking; low weight and BMI; estrogen deficiency caused by early (age younger than 45 years) menopause, bilateral oophorectomy, or prolonged (longer than 1 year) premenopausal amenorrhea; low lifelong calcium intake; alcoholism; impaired eyesight despite adequate correction; history of falls; inadequate physical activity All women: certain diseases or medical conditions and certain drugs associated with an increased risk of osteoporosis