Journal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

REVIEW NORMAL OVARIAN PHYSIOLOGY

Ovarian Hyperstimulation Syndrome: A Review of Pathophysiology

Peritoneal Fluid The marked degree of peritoneal permeability seen in the OHSS is reflected to a much lesser degree in the variations in peritoneal fluid volume that have been o b s e r v e d in normal m e n s t r u a t i n g women. Novak first reported the presence of peritoneal fluid in normal women in 1922 (23) and Bissel noted that changes in the amount of this peritoneal fluid occurred around the time of ovulation (24). After ovulation, Maathuis et al. found the concentrations of estradiol and progesterone in peritoneal fluid to be significantly higher than plasma levels (25). This finding was verified by Koninckx et al. (26), who suggested that prior to vascularization, the secretion of the early corpus luteum was directed preferentially toward the peritoneal cavity presumably from the thecal capillaries and the ovulating ostium. Interestingly women with the luteinized unruptured follicle syndrome had low peritoneal fluid concentrations of estradiol and progesterone while still having a quantity of peritoneal fluid that was similar to that of ovulatory women (27,28). The volume of peritoneal fluid was found to be directly related to cyclic ovarian activity; it was consistently low in normal males (25), postmenopausal women (26-28), and women on oral contraceptives (26-28). In normal, ovulatory women, the volume of peritoneal fluid was diminutive in the early proliferative phase and increased imperceptibly until the time of ovulation. Following ovulation, there was a sudden increase in the volume of peritoneal fluid that lingered throughout the luteal phase and diminished at the commencement of menses (2628). Since this peritoneal fluid production was not dependent on the patency or presence of the fallopian tubes or uterus, its origin was felt to be ovarian or peritoneal (26,27). One likely mechanism for these cyclical peritoneal fluid changes may be related to marked increase in capillary permeability induced by intraovarian angioneogenesis (29).

PAUL A. BERGH 1 and DANIEL NAVOT 1'~ INTRODUCTION Ovarian hyperstimulation syndrome (OHSS) remains the most serious complication of ovulation induction (OI). In its severest, critical form it is characterized by enormous, cystic ovarian enlargement with massive extravascular fluid shifts and secondary intravascular volume depletion (1,2). This acute fluid shift into third spaces, with accompanying electrolyte imbalance, and hemoconcentration is largely responsible for the serious morbidity (3-6) and occasional mortality (7,8) seen in OHSS. Although the pathophysiology of this syndrome has not been completely elucidated, the underlying mechanism responsible for the clinical manifestation of OHSS appears to be an increase in capillary permeability of mesothelial surfaces (9). Risk factors (10,11)for the OHSS include high serum estradiol (Ez) levels (2,12-14) and multiple immature and intermediate follicles (15-17). Patients with polycystic ovarian disease (PCO) are well-known to be predisposed to this syndrome (18-20). In addition, the OHSS is almost restricted to cycles with either exogenous or endogenous pregnancy-derived, human chorionic gonadotropin (hCG) stimulation (1,2,21,22). The events of OI leading up to the development of the OHSS, for the most part, represent an exaggeration of the normal process of follicular development and ovulation. Thus, a brief and selected review of the normal menstrual cycle is warranted before examining the phenomenon of OHSS. 1 Department of Obstetrics Gynecology and Reproductive Science, Mount Sinai Medical Center, New York, New York 10029. z To whom correspondence should be addressed at Box 1175, Department of OBS/GYN, Mt. Sinai Medical Center, One Gustave Levy Place, New York, New York 10029.

Ovarian Angiogenesis Folliculogenesis and maturation, ovulation, and corpus luteum formation are associated with a vig429

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orous increase in capillary permeability secondary to angiogenesis (29). The acquisition of an independent blood supply for the theca tissue of the selected secondary follicle is a prerequisite for continued maturation and dominance (30,31). Furthermore, ovarian and corpus luteum formation involve marked changes in capillary permeability and neovascularization of the granulosa tissue (31,32). The work of diZerega and Hodgen (33) as well as Zeleznick et al. (34) established the presence of an increased density of blood vessels in the infrastructure of the dominant follicle in primates. The exhibition of perifollicular blood vessels during the development and demise of rat ovarian follicles was first described by Basset (35). He noted the growth of angiogenic buds from these perifollicular vessels extending into the granulosa layer with an associated rapid increase in capillary permeability. Numerous others have demonstrated the presence of angiogenic activity in the follicular fluid of various species including humans (29,36--42). Sato et al. demonstrated a link between gonadotropins and ovarian angiogenic capacity (38). Interestingly, Frederick et al. (42) found that follicular fluid from small porcine follicles contained greater chemotactic activity (induction of fetal aortic endothelial cell migration) than follicular fluid from medium or large follicles. In addition, they speculated that this porcine follicular fluid angiogenic substance appears to consist of an active low molecular weight angiogenic factor combined with a higher molecular weight carrier protein. Similar observations have been made in human follicular fluid of angiogenic activity in high (45,000 to 60,000) and low (< 1500) molecular weight fractions (42). Fernandez et al. discovered high levels of reninlike activity in preovulatory follicular fluid (43). Angiotensin II, the active end product of the reninangiotensin cascade, has been shown to have a wide range of actions including vasoconstriction, aldosterone biosynthesis, prostaglandin formation (44), enhanced steroidogenesis (45), increased vascular permeability, and angiogenesis (46). Conceivably, angiotensin II may play a major role as an intraovarian angiogenic factor. In addition, angiotensin II could be implicated in ovarian steroid biosynthesis, follicular rupture, and ovum extrusion. THE RENIN-ANGIOTENSIN SYSTEM Renin and its high molecular weight precursor, prorenin, circulate in plasma (47-49). Prorenin,

BERGH AND NAVOT

contrary to most hormone precursors, can be found in plasma at concentrations up to 10 times that of active renin (47). In addition, while the kidney appears to be the primary source of active renin, prorenin originates from a variety of other tissues including the placenta and the ovary (50-53). The richest source of active renin is the juxtaglomerular cells in the walls of the afferent arterioles of the kidney. These cells secrete renin directly into the arterial blood of the kidney and are thus considered endocrine cells. However, renin, unlike other hormones, is actually an acid protease enzyme which is responsible for the formation of the active hormones, the angiotensins, by specifically cleaving the leucine-leucine peptide bond at the amino terminus between position 10 and position 11 of its substrate, the glycoprotein angiotensinogen (Fig. 1). Angiotensinogen is found in the a2-globulin fraction of the plasma and is synthesized by the liver. While the rate of angiotensin II formation is dependent on the plasma renin concentration, the rate of angiotensin formation is also vulnerable to variations in the concentration of angiotensinogen in the plasma since the latter is present in amounts less than required for the maximal reaction velocity. Thus, because the production of angiotensinogen by the liver is increased by estrogens and glucocorticoids, the concentration of angiotensins in plasma rises in pregnancy and with the use of oral contraceptives (54). This cleavage of angiotensinogen results in the formation of the decapeptide angiotensin I, on which renin has no further hydrolytic action (55) (see Fig. 1). This decapeptide has little pharmacologic activity; its principal function is to serve as the substrate for the formation of the octapeptide angiotensin II. The zinc-containing exopeptidase [angiotensin converting enzyme (ACE) or peptidyl dipeptidase] catalyzes the cleavage of two peptides from the carboxyl-terminal region of angiotensin I, resulting in the much more potent angiotensin II. This dipeptide cleavage is not specific to angiotensin I and other substrates for this enzyme include bradykinin, enkephalins, and substance P. While the converting enzyme is found in most tissues in the body, the very rapid conversion of angiotensin I to angiotensin II is due to the activity of the tissue bound enzyme present on the luminal aspect of the vascular endothelial cells. Although up to 80% of angiotensin I is metabolized in a single pass through the pulmonary bed, extrapulmonary conversion is brisk as well. Angiotensin II is rapidly catabolized (for the most part by widely Journal o f Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

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Angiotensinogen 1

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distributed aminopeptidases), with a half-life of about 4 min. The resulting products include both a heptapeptide (also known as angiotensin III) which retains most of the activity of its precursor and a pharmacologically inactive pentapeptide.

THE OVARIAN RENIN-ANGIOTENSIN SYSTEM Sealey and co-workers first noted the periodicity of prorenin synchronized with luteinizing hormone and progesterone in the normal human menstrual cycle (56-58). They noted a stable, baseline level of plasma prorenin during the follicular phase. Near the midcycle luteinizing hormone (LH) peak, there was a consistent two- to fourfold increase in prorenin starting 8-16 hr after the initiation of the LH surge and returning to baseline approximately 16 hr after LH. A second, smaller midluteal rise in prorenin was noted coinciding with the time of the luteal-phase progesterone peak. This second, midluteal peak in plasma prorenin was related to changes in levels of active renin. Active renin levels have been found to be higher in the midluteal phase. This fluctuation of active renin appear to be secondary to the natriuretic effect (59,60) of progesterone (61--63). Sealey et al. speculate that since diuretics cause an increase in prorenin, the diuretic effect of progesterone (as a natriuretic and partial antagonist of aldosterone) may augment the increased midluteal levels of prorenin, which thus would be of renal origin (64,65). Thus, the pattern of prorenin Journal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

levels seen in the menstrual cycle may be related to two independent factors: the initial increase, associated with the LH surge; and the midluteal rise, related to progesterone. The temporal relationship of the former to LH suggests that LH may stimulate prorenin production. Evidence to support this concept includes the finding that during controlled ovarian hyperstimulation, plasma prorenin increases when human chorionic gonadotropin (hCG) is given to induce ovulation (66,67). In addition, plasma prorenin, similar to the levels of hCG, increases rapidly within 20 days following conception (68,69). The ovary appears to be the source of this g o n a d o t r o p i n - d e p e n d e n t p r o r e n i n discharge. Fernandez and co-workers as well as Glorioso et al. demonstrated preovulatory follicular fluid levels of prorenin up to 12 times higher than those of plasma prorenin after gonadotropin stimulation (43,70). The amplitude of the midcycle rise of prorenin in response to hCG is related to the number of ovarian follicles. Also, the degree of rise of conceptual prorenin appears to be related not only to the level of hCG stimulation (number of conceptuses) but also to the number of corpora lutea produced during the conception cycle (68,69). The lack of increased prorenin secretion in pregnant women without ovarian function lends further support to the concept of the ovary as the source of prorenin (68,69). Through the elaboration of angiotensin II, the ovarian prorenin system may play a crucial role in normal ovarian physiology and thus may be implicated in the pathophysiology of the OHSS (Fig. 2). Indeed, Navot et al. found a direct correlation between the plasma

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hCG

Ovarian P r o r e n i n Renin Substrate

Active Renin Angiotensin I Angiotensin II PG's

Cytokines Fig. 2. Schematic outlining role of renin-angiotensin system in the pathogenesis of OHSS.

renin levels and the severity of the OHSS and thus established the link between the renin-angiotensin cascade and OHSS (71). A recent report by Ong et al. of patients with OHSS found pronounced elevations in plasma renin activity and plasma aldosterone concentrations despite significant therapeutic plasma volume expansion (72). Their findings support the concept that the mobilization of the reninangiotensin system in the OHSS is a primary phenomenon rather then the repercussion of plasma volume contraction as suggested by others (73). In addition they argue that this sheds light on the seeming incongruity of hyperaldosteronism in OHSS that does not respond or even worsens in the face of correction or overcorrection of hypovolemia (74,75). Although angiotensin II is best known for its pressor affect, its ability to enhance vascular permeability and initiate angiogenesis would account for a pivotal role in both the normal ovulatory peritoneal fluid accumulation and the dramatic fluid shifts seen in the OHSS. Angiotensin II acts to increase capillary filtration pressure by constricting postcapillary venules (76). Additional increases in vascular permeability in larger arterioles are caused by the separation of endothelial cells by a possible contractile response (77). Overall there is a marked decrease in blood volume and an increase in extravascular fluid and flow of lymph. An increase in capillary permeability is also seen in relation to angiotensin II's ability to induce angiogenesis. Initially, indirect evidence that the renin-angiotensin

system was involved in renal angiogenesis was provided by Cuttino et al. and Ilich and co-workers (78,79). More recently, Fernandez and co-workers demonstrated that angiotensin II facilitated the activation of preexisting collateral vascular pathways and significantly stimulated new vessel formation (46).

ALTERNATE MEDIATORS OF OHSS

Prostaglandins Prostagtandins (PG) have been suggested as likely candidates in the pathogenesis of OHSS (2,80,81). The stimulation of prostaglandin production by angiotensin II (44) may serve as an additional mechanism for the latter in the induction of OHSS. However, indomethacin in pharmacologic doses failed to prevent ascites and ovarian enlargement in rabbits despite its ability to suppress ovarian prostaglandin formation (82). Similarly, human trials of indomethacin for the treatment of the OHSS have been disappointing (83) (Fig. 2). Histamines Histamine has also been proposed as a possible mediator of the OHSS, and treatment with H~ blockers was evaluated in the rabbit (84-86). Although these animal studies yielded promising reJournal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

OVARIAN HYPERSTIMULATION SYNDROME

sults in reduction of ascites and ovarian size in OHSS, more recent reports have been less promising. Erlick and co-workers demonstrated no difference in histamine levels between rabbits in whom OHSS was induced and controls (87). In another rabbit study, Zaides et al., using two different H1 receptor blockers failed to detect any role for serotonin in the pathogenesis of OHSS (88).

Cytokines A new and exciting area of ovarian physiology, the interaction between the immune system and the gonads, may shed fresh insights on the pathophysiology of the OHSS. Recently, there have been numerous reports regarding the cytokine-mediated regulation of ovarian function. Cytokines are polypeptide products, primarily" of activated immune and mesenchymal cells, that have been shown to affect the development and function of distinct cells of assorted derivation other than those of the immune system (89). Most recent work regarding this cytokine modulation of ovarian function has focused on the interleukin family. It is well established that white cells are inhabitants of the ovary. While the macrophage's presence within the interfollicular ovarian compartment is fairly constant (90), other components show dramatic variations in white cell content with the menstrual cycle. During the latter period of the follicular phase, there is a marked infiltration of mast cells that degranulate in response to the preovulatory LH surge (91). This is followed by the orderly migration of granulocytes, T lymphocytes, and phagocytic macrophages. Analysis of follicular fluid aspirated from women undergoing in vitro fertilization revealed that macrophages and monocytes compromise 5-15% of the cell population found in human follicular fluid (92). This apparent acute inflammatory reaction is likely to be secondary to the increased periovulatory follicular neovascularization combined with the release of follicular chemotactic factors (93). The presence of cytokines within the ovary does not appear to depend only on lymphocytic infiltration, as the oocyte may contribute to their production as well. Zolti et at. demonstrated the expression of various cytokines in the oocyte and early embryo (94). Interleukin-1 (IL-1) is an activated macrophagederived cytokine, previously known as lymphocyte activating factor. While the macrophage is the principal source for this polypeptide, other tissues (vasJournal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

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cular, epithelial, lymphoid, epidermal, and possibly granulosa cells) produce IL-1. IL-1 is responsible for a wide variety of biologic activities. It plays an important role in the pathogenesis of many diseases and mediates a broad spectrum of systemic changes involved in the host response to infection, inflammation, immunologic challenge, and injury° It exists in two structurally related but distinct forms, IL-I~ and IL-I~, that are the translational products of separate genes, both located on chromosome 2 (95,96). Although the beta form appears to be more potent, both forms of IL-1 have been found to suppress the functional and morphological luteinization of cultured murine and porcine granulosa cells (97103), while at the same time they stimulate the proliferation of these cells (103). Furthermore, IL-I~ has been shown to enhance the ability of hCG to stimulate thecal progesterone production in vitro by healthy or atretic preovulatory follicles (104). Interleukin-l[~, on the other hand, has been shown to be a potent stimulator of prostaglandin synthesis in bovine luteal cells (105). Hurwitz et aI. recently presented evidence that the intraovarian IL-1 system is highly compartmentalized and may modulate the intraovarian regulation of somatic ovarian cell differentiation and thus follicular maturation (106). Ab though this cytokine appears to play primarily a paracrine role in ovarian physiology, the detection of IL-1 in the plasma of women after ovulation has led to the hypothesis for a possible endocrine function (107). Another cytokine, interleukin-6 (IL-6), was first described as a type of interferon that was purified with hepatocyte and hybridoma growth factor. Similar to IL- 1, this polypeptide has a medley of effects including the modulation of inflammatory reactions involving various cell lineages including the immune system (89). The mRNA of IL-6 has been reported to be produced in vivo in two, serf-limiting angiogenic processes: (i) the neovascularization accompanying ovarian follicular development and (ii) the formation of the capillary network in the maternal decidua following embryonic implantation (108). This limited expression of IL-6 suggests a role for this cytokine in reproductive angiogenesis. Although these cytokines have not been examined in the context of the OHSS, evidence continues to accumulate on their importance in the modulation of most aspects of ovarian physiology. It is not unreasonable to anticipate a significant role for these ovarian regulators in the pathophysiology of OHSS (E. Adashi, personal communication).

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HEMODYNAMICS OF OHSS The marked shift of intravascular fluid into third spaces is primarily responsible for the morbidity and occasional mortality of the OHSS (Fig. 3). This disturbance in normal hemodynamics has a wide range of consequences including ascites and pleural effusions (2,6,13), electrolyte imbalance, liver (3, 109) and kidney (2) damage, and thromboembolic phenomena (7,8,110). This broad expanse of systemic effects resulting from the OHSS is ultimately derived from a rapid and relentless depletion of intravascular plasma volume. Thus, the single most important parameter that indicates the severity of the OHSS is the hematocrit (83). It is well accepted that in the face of a constant red cell volume (RCV), a rising hematocrit signifies a fall in plasma volume (111-113). In addition, the mistaken belief that the magnitude of change in the hematocrit is directly proportional to the change in plasma volume has been propagated in the literature over many years (114-121). In an elegant mathematical derivation based on actual and theoretical data, van Beaumont illustrates the true relationship between hematocrit and plasma volume (122). It appears that when the RCV remains constant, the change in hematocrit can never be numerically commensurate with the change in plasma volume. The percentage change in plasma volume is described by the product of a proportionality factor and the percentage difference between the original and the final hematocrit ratios as illustrated by the following equation:

%AP-

100 100(Hi-//2) x % (100 - H1) H2

where %AP is the percentage change in plasma volume, H1 is the initial hematocrit, and HE is the final hematocrit. The nomogram in Fig. 4 is derived from this equation and can be used to determine actual plasma volume changes based on interval hematocrit measurements. Since the hematocrit is actually the ratio between RCV and total blood volume (RCV + plasma volume), the change in plasma volume must always be larger than the change reflected by the hematocrit. Thus a change of 2 points in the hematocrit from 45 to 47% is four times smaller than the actual 8% drop in plasma volume. This is extremely important to keep in mind when treating patients with OHSS. Any increase in the hematocrit as it approaches 45% does not accurately reflect the magnitude of plasma volume depletion and thus the seriousness of the patient's condition. One should therefore not be lulled into a false sense of security by small incremental rises in hematocrit above 40-45%. Likewise, in the face of hemoconcentration, small drops in the hematocrit may represent significant improvements in plasma volume.

CONCLUSION OHSS is the most serious complication of ovarian stimulation and it reflects the amplification of the Intravascular

Space ular Volume

md tein Depletion

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Blood Viscosity Thromboembolic Phenomena Tense Ascites Fig. 3. Schematic detailing the complex hemodynamic changes resulting from the OHSS. Journal of Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

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%~ PV I1 ,22 21 2O 19 18 17 16 15 14 13 12

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usual events of ovarian physiology. As such, it magnifies the normal phenomenon of follicular recruitment and growth, ovulation, and corpus luteum formation through the window of events comprising the OHSS. The most plausible mediator for the increased ovarian and peritoneal permeability with resultant massive fluid shifts is angiotensin II. The iatrogenic stimulation of multiple follicles amplifies the gonadotropin-dependent, local ovarian reninangiotensin system and thus the production of angiotensin II. Through its effects on capillary hydrostatic pressure, capillary permeability, and angiogenesis, this powerful peptide mediates the marked ascites, ovarian enlargement, and intravascular depletion responsible for the morbidity of the OHSS. The single most important parameter which indicates the severity of the OHSS is the hematocrit; thus when following these patients, it is very important to keep in mind that the change in plasma volume will always be larger than the change reflected by the hematocrit. Journal o f Assisted Reproduction and Genetics, Vol. 9, No. 5, 1992

Of the possible alternate mediators of the OHSS, the most promising area appears to be the interaction between the immune system and the gonads. The insight gained on this important and exciting new area of ovarian physiology will surely lead to an improved understanding of the pathophysiology of the ovarian hyperstimulation syndrome. REFERENCES 1. Rabau E, David A, Sen- DM, Mashiach S, Lunenfeld B: Human menopausal gonadotropins for anovulation and sterily. Results of 7 years of treatment. Am J Obstet Gynecol 1967;96:92-98 2. Schenker JG, Weinstein D: Ovarian hyperstimulation syndrome: A current survey. Fertil Steril 1978;30:255-268 3. Balasch J, Carmona F, Llach J, Arroyo V, Jove I, Vanerell JA: Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome. Hum Reprod 1990;5:348-351 4. Younis JS, Zeevi D, Rabinowitz R, Laufer N, Schenker JG: Transient liver function test abnormalities of ovarian hyperstimulation syndrome. Fertil Steril 1988;50:176-178 5. Rizk B, Meagher S, Fisher A: Severe ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum Reprod 1990;5:697-698 6. Padilla SL, Zamaria S, Baramki TA, Garcia JE: Abdominal paracentesis for the ovarian hyperstimulation syndrome with severe pulmonary compromise. Fertil Steril 1990;53: 365-367 7. Moses M, Bogowsky H, Anteby E, et al.: Thromboembolic phenomena after ovarian stimulation with human menopausal gonadotropins. Lancet 1965;2:1213-1215 8. Crooke AC, Butt WR, Carrington SP, et aI.: Pregnancy in women with secondary amenorrhea treated with human gonadotropins. Lancet 1964;1:184-188 9. Polishuk WZ, Schenker JG: Ovarian overstimutation syndrome. Fertil Steril 1969;20:443-450 10. Navot D, Relou A, Birkenfeld A, Rabinowitz R, Brzezinski A, Margalioth EJ: Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988;159:210-215 11. Navot D, Bergh PA, Laufer N: Ovarian hyperstimulation syndrome in novel reproductive technologies: Prevention and treatment. Fertil Steril 1992;58:249-261 12. Haning RV Jr, Boebnlein LM, Carlson IH, Kuzman DL, Zweibel WJ: Diagnosis-specific serum 17 beta-estradiol (E 2) upper limits for treatment with menotropins using a 125-I directed E 2 assay. Fertil Steril 1984;42:882-889 13. Golan A, Ron-E1, Herman A, Softer Y, Weinraub Z, Caspi E: Ovarian hyperstimulation syndrome: An update review. Obstet Gynecol Surv 1989;6:430--440 14. Blankenstein J, Mashiach S, Lunenfeld B: Induction of ovulation with gonadotropins. In Induction of Ovulation and In Vitro Fertilization, J Blankenstein, S Mashiach, B Lunenfeld (eds). Chicago, Yearbook Medical, 1986, p 122 15. Tal J, Paz B, Samberg I, Lazarov N, Shaft M: Ultrasonographic and clinical correlates of menotropins versus sequential clomiphene citrate: Menotropin therapy for induction of ovulation. Fertil Steril 1985;44:342-349

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