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PubMed1998

Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. The European Recombinant Human LH Study Group.

The efficacy of recombinant human LH (rhLH) for supporting human (rhFSH)-induced follicular development was investigated in hypogonadotropic hypogonadal women (WHO group I anovulation). Patients (n = 38) were randomized to receive rhLH (0, 25, 75, or 225 IU/day) in addition to a fixed dose of rhFSH (150 IU/day). rhLH was found 1) to promote dose-related increases in estradiol (E2) and androstenedione secretion by rhFSH-induced follicles, i.e. serum concentrations on the last day of FSH administration were 65 +/- 4, 195 +/- 94, 1392 +/- 585, and 2441 +/- 904 pmol/L for E2 and 3.6 +/- 0.9, 5.1 +/- 1.3, 6.4 +/- 1.3, and 6.7 +/- 1.3 nmol/L for androstenedione for patients treated with 0, 25, 75, and 225 IU rhLH, respectively; 2) to increase ovarian sensitivity to FSH, as demonstrated by the proportion of patients who developed follicles after the administration of a fixed dose of FSH, i.e. 1 of 8, 3 of 7, 7 of 9, and 8 of 10 in patients treated with 0, 25, 75, and 225 IU rhLH, respectively; and 3) to enhance the ability of these follicles to luteinize when exposed to hCG. A daily dose of 75 IU rhLH was effective in the majority of women in promoting optimal follicular development (defined as > or = 1 follicle > or = 17 mm; E2, > or = 400 pmol/L; midluteal phase progesterone, > or = 25 nmol/L) and maximal endometrial growth. A minority of patients may require up to 225 IU/day. rhLH, given sc at a dose up to 225 IU/day, was not immunogenic and was well tolerated.

Adult↗
PubMed2005

Alterations in reproductive function in SRC tyrosine kinase knockout mice.

The role of Src tyrosine kinase in regulating reproductive processes in female mice was investigated using Src wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice. Ovarian Src kinase activity transiently increased in Src +/+ mice following eCG administration. Src knockout mice were infertile. Estrous cycles and vaginal opening in Src knockouts were variable and altered compared with Src +/+ and +/- mice. Follicle development was compromised in Src knockout mice as evidenced by reduced numbers of large pre-antral and antral follicles compared to Src +/+ mice. Corpora lutea were not observed in the ovaries of Src knockout mice; however, administration of eCG and hCG did result in ovulation. Serum LH and FSH on d 40 and 52 of age did not differ between Src wild-type and knockout females. Results from these studies reveal that female Src knockout mice are infertile due to reduced follicle development and anovulation.

Animals↗
PubMed2006

Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment.

Polycystic ovary syndrome accounts for more than 75% of cases of anovulatory infertility. The mechanism of anovulation is uncertain but there is evidence that arrested antral follicle development is associated with the abnormal endocrine profile, in particular the interaction of insulin and LH on granulosa cell differentiation. In terms of management, induction of ovulation can be achieved in most cases by the use of antiestrogens. Treatment of clomiphene-resistant subjects is difficult; conventional doses of gonadotropins are associated with high rates of ovarian hyperstimulation syndrome and multiple pregnancy. On the other hand, low-dose gonadotropin therapy has proven effective in inducing unifollicular ovulation and, in this review, we present, in detail, a recent analysis the results from this center. The cumulative conception rate after six cycles was more than 50% and, importantly, the multiple pregnancy rate was only 3%. Weight reduction in obese subjects with PCOS not only increases the chance of fertility but may also improve the long-term prognosis with regard to development of diabetes. Insulin-sensitizing drugs such as metformin may also have a place in treatment of PCOS.

Adult↗
PubMed1982

[The ovulation-inducing effect of CB-154 on normoprolactinemic anovulatory subjects (author's transl)].

Several investigators have reported that CB-154 induces ovulation in patients with normoprolactinemic anovulation as well as those with hyperprolactinemic amenorrhea. In the present research, the ovulation-inducing effects of CB-154 were studied in normoprolactinemic subjects with special reference to the feedback effect of estradiol on LH release. Thirty female subjects aged 20 approximately 32 years with ovulatory disturbances were studied. Basal serum PRL, LH and FSH were determined by radioimmunoassay, and both hyperprolactinemic and hypergonadotropic anovulatory patients were excluded. A 2mg dose of estradiol benzoate was administered intramuscularly to each subject and 8ml samples of venous blood were taken at 0, 6, 24, 30, 48, 54, 72, 78 hr. The subjects under study were divided into two groups, A and B, according to the effect the estradiol benzoate had an LH release. Group A subjects (nine in all) failed to show any positive feedback release of LH in response to the estradiol benzoate. Group B subjects (twenty-one in all) showed a more than twofold increase in circulating LH as compared with the initial serum LH value, and this was taken as an indication of positive feedback release. All the subjects in group B were given clomiphene (50 approximately 100mg daily for five days). The clomiphene therapy was effective in eleven subjects, and four became pregnant (three in the first or second cycle of treatment and one in the third). The therapy was ineffective in the remaining six subjects, four of whom were diagnosed as suffering from polycystic ovary syndrome. Clomiphene was judged to be effective when the subjects undergoing therapy with this drug ovulated during three successive treatment cycles, and ineffective when the subjects did not fulfill this criterion (criterion for effectiveness of clomiphene). With the exception of four cases of polycystic ovary syndrome and three pregnancies which occurred in the first or second cycle, the rate of effectiveness of clomiphene in group B was 12 out of 14. It was concluded from these results that clomiphene was effective in group B subjects except in cases of polycystic ovary syndrome. Treatment with clomiphene alone was effective in none of the seven subjects in group A. However, administration of CB-154 for several weeks prior to and during the clomiphene treatment cycle (combined therapy of CB-154 and clomiphene) led to remarkably improved ovulation rates in five subjects in group A. Four patients in group A were selected, and given estradiol benzoate prior to (control) and during (study) CB-154 administration. In each case administration of CB-154 elicited marked positive feedback release of LH as compared with the control period, that is to say, CB-154 transformed group A patients into group B patients. This effect of CB-154 may explain why therapy combining CB-154 and clomiphene improved ovulation rates in group A...

Anovulation↗
PubMed1993

[A study with diagnostic standard of occult hyperprolactinemia (OHP) and the effect of bromocriptine administration].

It is well known that the transient excessive increase of serum prolactin level is harmful for the mechanism of ovulation or the steroidogenesis of the ovaries. The pathogenesis of latent or occult hyperprolactinemia (OHP) has been investigated recently. The present study was conducted to determine the diagnostic standard of OHP, and to elucidate the efficacy of bromocriptine administration for the treatment of OHP and other ovulatory disturbances. 110 cases of hypothalamic anovulations were selected from 385 cases of infertile patients by the LH-RH and TRH loading tests. Bromocriptine (5mg/day) was administered to all of the subjects for more than three months, and the efficacy of the bromocriptine administration was investigated. Follicular development was observed by transvaginal ultrasonography (mature follicular diameters > or = 20mm), and also luteal function was estimated by the duration of the luteal phase in the BBT charts (high phase > or = 12 days), the mid-luteal serum estradiol (> or = 200pg/ml) and progesterone (> or = 10ng/ml) levels. The subjects were divided into two groups: group A, bromocriptine effective patients (63 cases) and group B, bromocriptine non effective patients (47 cases). The results of the LH-RH and TRH loading tests were compared between these two groups. Serum prolactin levels at 30 min. after TRH loading (PRL30) in group B (61.5 +/- 28.3 vs. 38.0 +/- 19.3ng/ml, p < 0.01). At the cut-off points of 50, 60 and 70ng/ml over in the values of the PRL, the efficacies of the bromocriptine administration were 77.4, 78.9 and 88.5%, respectively. From these facts, it was thought suitable that the diagnostic standard of OHP was PRL30 > or = 70ng/ml, and values of PRL30 from 50 to 70ng/ml were borderline cases of OHP. The efficacy of the bromocriptine administration in the cases without OHP (n = 57) was also investigated. Serum LH levels at 30 min. after LH-RH loading (LH30) were compared between the cases of the bromocriptine effective (n = 22) and non effective (n = 35). As a result, the LH30 of the former was significantly higher than that of the latter (96.5 +/- 64.2 vs. 45.1 +/- 31.5mIU/ml, p < 0.005). In conclusion, the diagnostic standard of OHP was determined as PRL30 > or = 70ng/ml (borderline: 50 > 70ng/ml), and bromocriptine administration was effective not only in cases of OHP, but also in cases of hyperreactivities of LH (so-called endocrinological PCOD).

Anovulation↗
PubMed1994

[The effect of occult hyperprolactinemia (OHP) on gonadotropin secretion system].

The present study was conducted to investigate the effects of the transient increase of serum prolactin levels on the gonadotropin secretion system in patients with occult hyperprolactinemia (OHP). 216 cases of normoprolactinemic hypothalamic anovulatious were selected by LH-RH and TRH loading tests, and 5mg/day of bromocriptine was administered for more than 8 weeks. The effectiveness of the bromocriptine administration was estimated by the ultrasonic examination of the follicular development. The endocrinological backgrounds were compared between bromocriptine effective (154 cases, group A) and non-effective (62 cases, group B) patients. Serum prolactin levels 30min. after LH-RH and TRH loading (PRL30 in group A were significantly higher than those of group B (74.1 +/- 36.5 vs. 38.0 +/- 18.2ng/ml, p < 0.01). From this result, it was thought that many of the OHP patients were selected in group A. Serum LH levels 30min. after loading test (LH30) in group A also increased compared to those of group B (65.0 +/- 66.5 vs. 43.1 +/- 34.3mIU/ml, p < 0.02). The LH/FSH ratio before loading was also higher in group A (1.3 +/- 0.6) than that of group B (1.0 +/- 0.5, p < 0.02). This fact showed that group A also contained patients with hyper-LH hypothalamic anovulation, which is known as the endocrinological PCOD. There were also significant inverse correlations between serum levels of prolactin and FSH in group A (before loading values: r = 0.272, 30min. after loading: r = 0.224, p < 0.01). By the administration of bromocriptine, serum prolactin levels decreased both in group A and B, and the elevated serum LH/FSH ratio (1.0 +/- 0.4, p < = 0.02), LH30 (46.1 +/- 37.0mIU/ml, p < 0.005) also decreased significantly. Serum levels of FSH in group A increased significantly with treatment (before loading: 5.4 +/- 2.6-->6.2 +/- 2.0, 30min. after loading: 10.6 +/- 6.0-->14.6 +/- 9.9mIU/ml, p < 0.005). From these facts, it was concluded that FSH secretion was suppressed even by a slight increase of serum prolactin levels which was usually seen in the OHP, and bromocriptine administration was effective not only for the suppression of serum prolactin and LH levels, but also for the improvement of FSH secretion in the OHP patients.

Anovulation↗
PubMed1999

Induction of ovulation by Sairei-to for polycystic ovary syndrome patients.

In anovulatory patients ovulation is usually induced by clomiphene citrate (CC) or gonadotropin therapy, but in the case of polycystic ovary syndrome (PCOS), diagnosed by the presence of several micropolycysts in the ovaries and a high LH/FSH ratio in the serum, CC is only minimally effective, and side effects are often a problem with gonadotropin therapy. In the present study we administered a Chinese herbal medicine Sairei-to which appears to have a steroidal effect in anovulatory PCOS patients. As a result of the treatment, serum LH and the LH/FSH ratio significantly decreased (P<0.01) and the ovulatory rate was 70.6%. Serum testosterone levels were within normal limits before the treatment, and did not significantly change during the treatment. Sairei-to may therefore be useful for the treatment of anovulation in PCOS patients.

Anovulation↗
PubMed2005

A case of ovulatory cycle-dependent symptoms in woman with previous interferon beta therapy.

A woman with a menstrual cycle-dependent fever (more than 38 degrees C) and severe fatigue that disrupted her ability to work was referred to our hospital. Six years ago, the patient received interferon beta injections (6,000,000 IU day-1x48 days) for the treatment of hepatitis C virus. Although the treatment was successful against the virus, the symptomatic fever occurred monthly since the third year after receiving the treatment. The symptoms occurred a few days after ovulation in every menstrual cycle. When the ovarian function was suppressed by GnRH agonist (GnRHa), the symptoms disappeared. While in anovulation, the patient received estrogen followed by estrogen with progestogen, which resembles the sex hormone milieu of a normal menstrual cycle without the LH surge; this treatment did not induce the symptoms. When human CG (hCG) was injected on the beginning day of estrogen with progestogen following treatment with estrogen alone, the previous symptoms reappeared. However, the hCG injection without estrogen priming did not induce the symptoms. These studies indicated that the LH surge after estrogen priming induced the symptoms. Changes in serum inflammatory cytokine levels (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) were examined during the ovulatory cycle and the interleukin-1 levels during the treatment. There were no significant changes on these levels in the febrile period. The patient experienced normal menstrual cycles after finishing the five-month GnRHa treatment. Although her symptoms still occur, they are mild and do not require further medical treatment.

Adult↗
PubMed1990

Ovarian response patterns to human menopausal gonadotropin in mixed hyperandrogenemia.

Twenty-eight hyperandrogenemic women suffering from infertility owing to chronic anovulation were treated with hMG. Only 7 patients exhibited the typical polycystic ovarian appearance of multiple subcortical cysts, however, a wide range (6-15 cm3) of ovarian volume was observed. The LH/FSH ratio was consistently lower than 2.5 and circulating androgens of both ovarian and adrenal origin were elevated. The 4 days dexamethasone suppression test showed more than 80% suppression of dehydroepiandrosterone-sulphate and a variable (40-60%) reduction of testosterone and androstenedione levels. Two different patterns of follicular development were observed in response to hMG. Sixteen patients exhibited polycystic ovarian reaction, whereas 12 women had a follicular growth pattern similar to that seen in hMG-stimulated normo-ovulatory subjects. Patients with polycystic ovarian reaction showed a significantly increased androstenedione response to hMG when compared with the other group. Moreover, the non-stimulated ovarian volume was found to be markedly greater than in subjects without polycystic reaction. Thus, ovarian stimulation of patients with mixed hyperandrogenemia may elucidate the presence of borderline polycystic ovaries; furthermore the increased accumulation of androstenedione may suggest an inherent ovarian failure.

Adult↗
PubMed1995

Adrenal androgen production in polycystic ovary syndrome.

Secondary PCOS may occur in association with disorders characterized by adrenal androgen excess, e.g. congenital adrenal hyperplasia. Primary PCOS is associated frequently with more subtle abnormalities in adrenal androgen status. However, it has not been established that the mild adrenal androgen occurring in PCOS is causally involved in the development of PCOS, although adrenal hyperresponsiveness to stimulation appears to be characteristic of PCOS. It remains to be clarified whether this is due to excess stimulation of the adrenal by the putative CASH, which with ACTH probably coordinates adrenal androgen steroidogenesis, or whether adrenal hyperresponsiveness occurs as a consequence of increased cortisol clearance with compensatory hypersecretion of ACTH, which is associated with excessive adrenal androgen production. The possibility also exists that the enzyme system responsible for 17-hydroxyprogesterone production and its conversion to androgens is excessively active and may occur as a common defect in the adrenal and ovaries as a consequence of a congenital disorder. For at least some patients, treatment with a nocturnal low-dose glucocorticoid is an effective form of treatment. Indeed, this is the only hormonal form of treatment for hirsutism that also facilitates fertility and pregnancy. It is possible that PCOS may occur as a consequence of any disorder in which anovulation is associated with normal or elevated oestrogen levels. For some patients with PCOS, mild adrenal androgen excess is probably primary to development of the disorder. Thus, a trial of treatment with low-dose glucocorticoid at night appears to be a reasonable option in susceptible patients who can probably be recognized by demonstration of an excessive androgen response to ACTH or metyrapone.

Adrenal Glands↗
PubMed1983

Control of ovulation in farm animals.

Examination of hormonal changes occurring in farm species at the onset of puberty, during the follicular phase of the oestrous cycle, and at those times when ovarian activity is re-established after periods of seasonal or lactational anoestrus, provides circumstantial evidence that the final phases of follicular development are dependent on a pattern of tonic (episodic) LH secretion. A suppression of episodic LH secretion is associated with periods of anovulation. Stimulation of tonic LH secretion by repeated injections of small doses of synthetic Gn-RH or purified LH restores normal reproductive function in all but deeply anoestrous animals. Continuous infusion of Gn-RH is as effective as repeated injections. It is suggested that an additional inadequacy, possibly endocrine, contributes to the anovulatory state in deep anoestrus.

Anestrus↗
PubMed1993

Changes in pituitary secretion during the early postnatal period and anovulatory syndrome induced by neonatal oestrogen or androgen in rats.

The following experiments were performed: (i) concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin in plasma were measured at 2, 5, 8, 10 and 15 days in female Wistar rats treated on the first day of life with 100 micrograms oestradiol benzoate or vehicle; (ii) females injected on day 1 with 100 micrograms of oestradiol benzoate or 1 mg of testosterone propionate and from day 1 to day 10 or 15 with FSH and LH were killed on day 90; (iii) females injected from day 1 to day 10 or 15 with prolactin or vehicle were killed on day 90; (iv) females injected on day 1 with oestradiol benzoate and from day 1 to day 15 with a luteinizing-hormone-releasing hormone (LHRH) agonist were killed on day 90; (v) groups of females injected on days 1, 4, 7, 10, 13 and 16 with an LHRH antagonist were killed on day 90. Onset of puberty, vaginal cycles, organ weights and hormonal plasma concentrations were measured. Females treated on the first day of life with 100 micrograms oestradiol showed inhibition of gonadotrophin secretion and stimulation of prolactin secretion during the neonatal period. Females injected on the first day of life with oestradiol benzoate or testosterone propionate showed, in adulthood, anovulation, ovarian atrophy, reduced FSH plasma concentrations, increased prolactin plasma concentrations and reduced pituitary prolactin content.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1998

Role of excitatory amino acid pathways in control of gonadotrophin secretion in adult female rats sterilized by neonatal administration of oestradiol or testosterone.

Administration of sex steroids to neonatal female rats resulted in anovulation and absence of positive and negative feedback between oestradiol and LH secretion. In the present experiments, the role of excitatory amino acids in the control of gonadotrophin secretion in anovulatory adult rats sterilized by neonatal administration of oestradiol benzoate or testosterone propionate (100 mg or 1.25 mg on the day of birth, respectively) was studied. Cyclic females in metoestrus were used as controls. Serum LH and FSH concentrations were measured at different times after i.p. administration of N-methyl-D-aspartic acid (NMDA), kainic acid (agonists of NMDA and kainate receptors, respectively), MK-801 or 6,7-dinitroquinoxaline-2,3-dione (DNQX) (antagonists of NMDA and kainate receptors, respectively). Experiments were also performed in control and sterilized females 1 week after ovariectomy. It was found that: (1) the effectiveness of NMDA and kainic acid in stimulating LH secretion was significantly higher in sterilized than in cyclic females; (2) ovariectomy increased LH secretion only in control females; (3) the stimulatory effect of NMDA and kainic acid on LH secretion after ovariectomy was observed only in sterilized females; (4) MK-801 and DNQX selectively decreased LH secretion in sterilized females; and (5) FSH secretion remained unaffected after NMDA or kainic acid administration in both control and sterilized females. In conclusion, the results obtained in sterilized females showed both a tonic release of endogenous excitatory amino acids and a greater responsiveness to NMDA and kainic acid than in controls.

Animals↗
PubMed2001

Oestrogenic effects of neonatal administration of raloxifene on hypothalamic-pituitary-gonadal axis in male and female rats.

Selective oestrogen receptor modulators constitute a family of drugs that are used increasingly in the management of oestrogen-associated pathology. Raloxifene is a selective oestrogen receptor modulator that is used to treat and prevent osteoporosis in post-menopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol concentrations have been widely analysed, but very few studies have investigated the possible actions of this drug on the central nervous system. The central nervous system of the newborn rat is very sensitive to oestrogen action. In this study a series of experiments was conducted to analyse the effects of different doses of raloxifene (50, 100, 250 or 500 microg per rat per day) administered to neonatal rats on days 1-5 of age. Female rats treated with raloxifene showed decreased gonadotrophin secretion, hyperprolactinaemia, advanced vaginal opening, decreased body weight, persistent presence of cornified epithelial cells in vaginal smears, anovulation, inhibition of positive feedback between oestradiol and LH, and infertility. Male rats showed delayed balanopreputial separation, reduced body weight and hyperprolactinaemia. All these changes resemble those obtained after neonatal administration of oestradiol benzoate, thus indicating, for the first time, that raloxifene exerts an oestrogenic action on the hypothalamic-pituitary structures controlling reproductive function in rats.

Aging↗
PubMed2001

Targeted disruption of the aromatase P450 gene (Cyp19) in mice and their ovarian and uterine responses to 17beta-oestradiol.

Aromatase P450 (CYP19) is an enzyme catalysing the conversion of androgens into oestrogens. We generated mice lacking aromatase activity (ArKO) by targeted disruption of Cyp19 and report the characteristic features of the ArKO ovaries and uteri as revealed by histological and biochemical analyses. ArKO females were totally infertile but there were as many developing follicles in their ovaries at 8 weeks of age as in wild-type ovaries. Nevertheless, no typical corpus luteum was observed in the ArKO ovaries. Electron microscopy revealed the presence of well-developed smooth endoplasmic reticulum, few lipid droplets and mitochondria with less organized tubular structures in the ArKO luteinized interstitial cells. These ultrastructural features were different from those of the wild-type interstitial cells, where there are many lipid droplets and mitochondria with well-developed tubular structures, characteristic of steroid-producing cells. When ArKO mice were supplemented with 17beta-oestradiol (E(2); 15 microg/mouse) every fourth day from 4 weeks of age for 1 month, increased numbers of follicles were observed in the ovaries as compared with those of untreated ArKO mice, although no typical corpus luteum was detectable. Ultrastructural analysis revealed the disappearance of the accumulated smooth endoplasmic reticulum in the luteinized interstitial cells after E(2 )supplementation. Transcripts of pro-apoptotic genes such as p53 and Bax genes were markedly elevated in the ArKO ovaries as compared with those of wild-type mice. Although E(2) supplementation did not cause suppression of the elevated expression of p53 and Bax mRNAs, it caused marked enhancement of expression levels of lactoferrin and progesterone receptor mRNAs in the uteri as well as increases in uterine wet weight. At 8 months of age, ArKO mice developed haemorrhages in the ovaries, in which follicles were nearly depleted, while age-matched wild-type females still had many ovarian follicles. Furthermore, macrophage-like cells were occasionally observed in the ArKO ovarian follicles. These results suggested that targeted disruption of Cyp19 caused anovulation and precocious depletion of ovarian follicles. Additionally, analysis of mice supplemented with E(2) demonstrated that E(2) apparently supports development of ovarian follicles, although it did not restore the defect in ovulation.

Animals↗
PubMed1986

Drugs in the treatment of female infertility. Recent advances.

Involuntary infertility is an increasing problem in this era of delayed childbearing. Fortunately, many advances have been made recently in the medical and surgical treatment of infertility. This article reviews the principal aetiologies of infertility and their treatments, and focuses on the current and future uses of ovulation-inducing drugs and other infertility treatments. Proper diagnosis of anovulation and luteal phase dysfunction is discussed together with a description of conventional treatments with clomiphene and human menopausal gonadotrophins (hMG). Recent advances including the use of synthetic gonadotrophin hormone-releasing hormone (GnRH), purified human follicle stimulating hormone and a combination of GnRH and hMG are described, along with the application of the same agents for enhanced follicular recruitment for in vitro fertilisation. In addition, several promising future developments for pharmacological induction of normal ovulation are also discussed.

Anovulation↗
PubMed2006

Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women.

For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of randomised controlled trials comparing clomifene with AIs are needed.

Anovulation↗
PubMed2004

Follicle-stimulating hormone in clinical practice: an update.

Follicle-stimulating hormone (FSH), a glycoprotein produced by the anterior pituitary gland, plays an important role in the regulation of fertility in both men and women. FSH is used clinically to treat women with anovulatory infertility, for controlled ovarian stimulation in women being treated with assisted reproductive technologies (ART), and in the treatment of male hypogonadotrophic hypogonadism. Urine-derived gonadotropin preparations containing variable amounts of FSH together with urinary proteins have been available for many years. More recently, FSH preparations produced using recombinant DNA technology have become available. Recombinant FSH has a high specific activity, high purity, and guaranteed consistency among batches. Two recombinant FSH preparations have been available for clinical use for some years: follitropin-alpha and follitropin-beta. The continuing development of recombinant FSH has recently resulted in a new presentation (follitropin-alpha filled by mass [FbM]). This product can be filled by mass (microg) with an activity (IU), reflecting exceptional consistency as a result of refinement and improvement in the manufacturing process, allowing the clinician to deliver a guaranteed dose of FSH. Experience with recombinant FSH in the treatment of male hypogonadotrophic hypogonadism is limited, but the available data suggest that recombinant FSH has a similar efficacy to urine-derived preparations (urofollitropin). In patients with WHO group I anovulatory infertility, the use of recombinant FSH to stimulate follicular development is effective and well tolerated. In patients with WHO group II anovulation, protocols based on recombinant FSH are more effective than conventional protocols using urofollitropin. Comparative studies and a meta-analysis have shown that recombinant FSH is more effective than urofollitropin for controlled ovarian stimulation in women undergoing ART. Pharmacoeconomic modeling indicates that follitropin-alpha is more cost effective than urofollitropin in a range of different healthcare systems. The available evidence from comparative studies of the two recombinant FSH preparations suggests that follitropin-alpha may have an advantage over follitropin-beta in terms of efficacy. Follitropin-alpha is superior to follitropin-beta in terms of local tolerability. Recent preliminary studies suggest an efficacy advantage for follitropin-alpha FbM compared with standard follitropin-alpha. The FbM presentation appears to represent an advance on standard preparations of recombinant FSH in terms of consistency and clinical efficacy.

Anovulation↗