Fig. 32.1
Etiology of hypogonadotropic hypogonadism
The role of leptin and adipokines in the adipocyte and fat metabolism and energy homeostasis and their impact on HPO axis are being increasingly recognized. Leptin, a 167-amino acid hormone, is secreted by adipocytes and its levels are positively correlated with body fat. Earlier, leptin was thought to be a solution for the obesity problem. Slowly, the role of leptin was better defined in energy-deficient states. In response to acute energy deprivation, the reproductive hormones are decreased in order to avoid high metabolic demands and pregnancy. This reduction is mediated through leptin [5]. Kisspeptin is another recently discovered neuromodulator that acts upstream of the GnRH to control pulsatile GnRH release. Kisspeptin is the main mediator which relays the negative and positive steroid feedbacks and information regarding body energy stores to hypothalamus. It has a key role to play in the onset of puberty. Kisspeptin may be the main mediator of metabolic and other factors affecting the hypothalamus [6]. Better elucidation of the role of leptin and kisspeptin in the neuroendocrine control of ovulation is likely to introduce newer therapeutic options in the management of HH and anovulation [6–8].
32.3 Clinical Presentation
The incidence of HH varies according to the population studied. In infertility clinics, the estimates vary from 1 to 3 % of all infertility and approximately 5 % of anovulatory infertility. The prevalence of congenital or idiopathic HH varies from one in 3,000 to 4,000 population and is two to five times more common in males [9].
Women with HH may present with delayed menarche, primary amenorrhea, or secondary amenorrhea. Genetic etiologies, e.g., Kallmann syndrome, present with primary amenorrhea. Sudden onset of secondary amenorrhea may antedate an event, e.g., parturition, irradiation, and surgery. It may have a more gradual onset when amenorrhea is associated with other systemic illnesses. The diagnosis of functional hypothalamic amenorrhea is quite obvious due to the presence of a significant history. History of weight loss and excessive exercise or dietary restriction in an anxious and stressed female presenting with amenorrhea are enough to indicate the diagnosis. The hypogonadotropic hypogonadism related to obesity is only recently recognized. Obesity affects establishment of a healthy HPO axis. In metabolically active obese women, obesity leads to hypogonadism [1] and in women with insulin resistance to PCOS.
The following case history is an illustrative example: a 30-year-old woman presented with progesterone withdrawal negative secondary amenorrhoea for 14 months. Her previous menstrual cycles were regular. She was married for 38 months and gave history of weight gain of (30 kg) since marriage. Her serum hormone levels were FSH 1.2 mIU/ml, LH 0.5 mIU/ml, and E2 15 pg/ml. Her ultrasound examination revealed a small uterus with linear hyperechoic endometrium. Both ovaries were very small but had 5–6 antral follicles of 1–2 mm diameter each. There was negligible stroma around the follicles. Her thyroid and adrenal functions were normal. She responded to ovulation induction with gonadotropins.
32.4 Ovulation Induction
Irrespective of the etiology of HH, the treatment to achieve fertility is very straightforward, i.e., ovulation induction (OI). Despite such profound hypoestrogenism and amenorrhea, these women respond very well to OI and achieve significantly high pregnancy rate. We discuss the topic under the following headings.
32.4.1 Confirmation of Diagnosis and the Underlying Etiology
Before treatment is started, it is mandatory to confirm the diagnosis. Amenorrheic women in whom progesterone (P) withdrawal is negative and combined estrogen (E) and progesterone (E + P) withdrawal is positive can have either hypergonadotropic amenorrhea or hypogonadotropic amenorrhea. Values in very low (i.e.,1 mIU) or low normal range of serum LH and FSH done during amenorrhea are enough to confirm the diagnosis. In case of any doubt, the test may be repeated to rule out a laboratory error. It is counterproductive to induce menstruation with E + P and then do the LH and FSH levels. One must take care to give a gap of at least 1 month between the test and the administration of estrogens or E + P preparations. Exogenous E or E + P preparations downregulate the pituitary and hypothalamus and may lead to false low serum levels of FSH and LH.
In cases of HH, serum E levels are extremely low. The absence of P withdrawal is enough for diagnosis and serum E level testing is not mandatory. Transvaginal ultrasound reveals a very small infantile type of uterus with thin, linear hyperechoic single-layer endometrium. In case the woman has been on E + P for hormone replacement therapy, the uterus may be of normal size and endometrium is better delineated. The ovaries are very small and difficult to locate, sometimes not even seen properly. No assessment of antral follicle count (AFC) is possible in a majority of cases.
A variant of HH with ovaries having PCOS morphology has been described [10, 11]. In such a woman, the ovaries are small but show multiple, small, one to two millimeter-sized follicles. These ovaries also respond to stimulation similar to that in HH but have a high risk of ovarian hyperstimulation syndrome (OHSS) [10, 11].
The case described below is a typical example: a 25-year-old woman presented with history of primary amenorrhea and primary infertility for three years. Her husband had severe oligoasthenozoospermia. She gave history of one abandoned in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) cycle. This was done to avoid OHSS because of the multifollicular development and high risk of OHSS. On reevaluation, her serum FSH level was 0.5mIU/ml and serum LH 0.1 mIU/ml. She gave history of induced menstrual bleeding with E + P, not with progesterone only. On ultrasound examination, her ovaries were medium sized and revealed 10–12 antral follicles of 1–6 mm size on each side and were devoid of any surrounding stroma. She was diagnosed as HH with polycystic ovaries. Second cycle of superovulation for IVF-ICSI was undertaken with recombinant FSH by default. The cycle had to be abandoned. There was follicular development of 8–10 follicles but her E2 levels remained very low. A third cycle with urinary gonadotropins containing both LH and FSH resulted in adequate stimulation for IVF-ICSI and twin live births.
After confirmation of the diagnosis, it is important to diagnose the underlying etiology. History of primary amenorrhea associated with anosmia is a clear pointer toward Kallmann syndrome. In the absence of anosmia, primary HH is labeled as idiopathic HH. A variety of genes have been identified for the idiopathic HH [12].
In case of suspected organic lesion, the history is very important. The diagnosis is easier in cases where there is a suggestive history, e.g., of accident, surgery, drugs, and systemic illness. In case a tumor or an infiltrative lesion of the brain is suspected, magnetic resonance imaging (MRI) of the pituitary region clinches the diagnosis. Despite all the tests, an idiopathic cause remains the most common diagnosis.
32.4.2 Distinguishing Between Hypothalamic and Pituitary Causes
It is important to distinguish the hypothalamic and the pituitary causes in case of HH because of 3 reasons. Firstly, pituitary lesions may have other concomitant endocrinopathies related to adrenal, thyroid, osmoregulation, or somatotropic axis. The importance of diagnosing other deficiencies is quite obvious. Secondly, any lesion in the pituitary may increase during the pregnancy and cause further complications due to the pressure effects. Thirdly, the method of OI may differ. While hypothalamic amenorrhea can be treated with both pulsatile GnRH and exogenous gonadotropins, HH of pituitary origin has only one option, i.e., the exogenous gonadotropins.
Genetic, systemic, functional, and idiopathic categories are generally hypothalamic in origin (see Fig 32.1). In these cases, the pituitary in addition to ovaries also remains responsive to exogenous GnRH. The pituitary origin of HH is mostly pathological. Neoplastic, infiltrative, vascular, or pituitary stalk lesions need to be ruled out (Fig. 32.1).
Appropriate history, blood tests to rule out comittant endocrinopathies, and an MRI of the brain are sufficient to arrive at the diagnosis. Adequacy of thyroid function can be assessed by serum thyroid-stimulating hormone (TSH) and triiodothyronine (T3) and thyroxine (T4) levels. Serum levels of growth hormone (GH), prolactin, cortisol, and dehydroepiandrosterone give reasonable estimate of other functions of pituitary, thyroid, and adrenal glands.
GnRH stimulation test is used to assess the responsiveness of pituitary. Serial samples of LH and FSH are taken after a bolus administration of native GnRH or GnRH analogue. An intact pituitary should respond with spurt of LH and FSH. Although widely used earlier, it does not give much additional information regarding pituitary adrenal axis or pituitary thyroid axis over the baseline hormone testing. An MRI of the sella is more useful. The role of GnRH stimulation test is to be reserved for those cases where basal hormone measurements are not helpful and where there is a strong clinical evidence of pituitary deficiency [1].
32.4.3 Exclusion of Other Infertility Factors
Before starting OI in these women, the couple must be evaluated to rule out other causes of infertility (infertility factors). The minimum required tests include the semen analysis and a hysterosalpingography (HSG) for tubal evaluation. Endometrial biopsy after an E + P-induced menstruation is indicated only if an infective pathology (e.g., genital tuberculosis) is suspected, such as in high-prevalent countries. There is no requirement of diagnostic laparoscopy or hysteroscopy.
Adequacy of the endometrial response may be assessed with a trial cycle of E administration. Estradiol valerate (E2) may be given twice or thrice a day. Transvaginal ultrasound done after 10 days of E2 reflects the endometrial response. This step can be omitted if there is history of good menstrual flow with E + P.
32.4.4 Physiological Basis of Ovulation Induction in Hypogonadotropic Hypogonadism
In women who do not desire pregnancy, the goal of therapy is to maintain adequate menstrual function with cyclic replacement of E + P. This will ensure general well-being and bone health. OI has to be undertaken in women desirous of pregnancy.
In HH of the pituitary origin, the only option available is to stimulate the ovary directly with the help of exogenous FSH and LH. This therapy is a substitution therapy, i.e., replacement of the deficient hormones. There is another option in hypothalamic amenorrhea. Pituitary can be stimulated with exogenous, native GnRH given in pulsatile manner mimicking the natural pulses. These GnRH pulses stimulate the pituitary to release LH and FSH, which is a more physiological technique.
FSH is the main stimulator of the ovarian follicles and granulosa cells and is indispensable. The role of LH is however not well understood. HH is one naturally occurring experimental model which has clarified the role of LH in ovulation induction. LH is essential for theca cell function. The synergistic but different effect of FSH and LH on granulosa and theca cells, respectively, is the basis of two cell-two gonadotropin theory. Estrogen is produced by granulosa cells under the influence of FSH from the androgen substrate, produced and supplied by theca cells under the influence of LH. LH is not only essential for steroid production but also for the maturation of oocyte and target tissue responses [13, 14]. It has been estimated that levels of 1–10 IU/L of LH should be sufficient to achieve these effects [13]. Moreover, a higher dose of LH may be detrimental and causes atresia of follicles—the LH ceiling effect [14].
Ovarian stimulation with recombinant FSH or FSH alone in women with HH results in follicular growth but E levels remain low [15, 16]. This is in contrast to successful stimulation with FSH alone in pituitary downregulated, normogonadotropic women. In these women, some residual LH activity remains despite downregulation; LH is essential in HH women who are devoid of any endogenous LH activity.
32.4.5 Pharmacological Agents
1.
Native GnRh
2.
Gonadotropins—urinary or recombinant
32.4.5.1 GnRh: Pharmacology
Native GnRh available in vials is to be given by subcutaneous (SC) or intravenous (IV) routes. A continuous infusion pump has to be used to deliver the precise dose at timely intervals. Local injection site irritation and visibility of the pump are the main disadvantages. Once very popular, pulsatile GnRh is used uncommonly these days. GnRh is not available in India for use.
32.4.5.2 Gonadotropins: Urinary or Recombinant
Either urinary or recombinant gonadotropins are used for ovulation induction. Each ampule of human menopausal gonadotropin (HMG) obtained from the urine of menopausal women contains 75 IU FSH and 75 IU of LH. These are available as HMG or highly purified HMG (HP-HMG) preparations containing 75 or 150 IU of FSH and LH per ampule as lyophilized powder. Urinary HMG can be given only by intramuscular route, while HP-HMG preparations can be given by subcutaneous SC route.
HMG factually contains some LH and mostly LH-like activity which is derived from variable amount of LH and mainly human chorionic gonadotropin (hCG). Urinary LH is highly unstable and has a variable potency. Thus, the LH-like activity is achieved by adding hCG [14].
Recombinant FSH (rFSH) and LH (rLH) are manufactured with genetic engineering technology using Chinese hamster ovary cell lines. Recombinant hormones are highly purified products with consistent batch to batch activity as compared to urinary products. Urinary products are a mixture of various bioisoforms of FSH, while rFSH contains only one isoform and also differs in terminal sialic acid content. Despite extensive purification, urinary FSH preparations retain some LH activity, while rFSH is devoid of any LH activity [16]. Recombinant FSH is available as single- or multiple-dose vials and pens which deliver a very small volume of solution with precision. Two products follitropin alpha and follitropin beta are currently available in the market. In India, many other companies have started marketing recombinant FSH products.
Recombinant LH is available only as 75 IU lyophilized powder. Both rFSH and rLH products are extremely well tolerated and user friendly in administration, although costlier than urinary products. Both products can be used through IM and SC routes. Following single administration, follitropin alpha has terminal half-life of 37 h and 74 % bioavailability [15]. Lutropin alpha has a half-life of about 18 h and bioavailability of 56 % [15].
Conventionally, rLH is given as a single daily injection. Twice daily regimen may have better endocrine profile in the stimulation cycles in HH women [17]. Recently, a mixture of follitropin alpha and lutropin alpha (follitropin alpha/lutropin alpha 150 IU/75 IU) has become available [18]. Early dose finding studies concluded that 75 IU rLH was effective in 94 % of women to achieve adequate follicular maturation and only a few would require a higher dose [19].
The choice between HMG and recombinant preparations depends on the cost and availability. When using high doses, recombinant preparation may have an edge. LH preparation is given separately; dose can be reduced to avoid LH ceiling effect [2]. Urinary products are efficient and cost-effective products. There are no randomized controlled trials comparing the urinary and recombinant products in HH women.
32.4.6 Ovulation Induction Regimens
The objectives of OI in HH are as follows:
1.
Monofollicular ovulation
2.
Adequate estradiol production
3.
Adequate endometrial preparation
4.
Timed coitus
32.4.6.1 Pulsatile GnRh
The treatment is suitable for women with intact pituitary, e.g., idiopathic HH or stress-induced amenorrhea [20]). The infusion of GnRh is done with the help of an automated pump at pulse frequency interval between 90 and 120 min [21]. GnRh can be given through IV (5–10 μg/ pulse) and SC (15–20 μg) routes per pulse. IV route is more successful than SC route [21]. Spontaneous LH surge is triggered by rising E levels. An hCG trigger may be given to induce ovulation although it is not mandatory. Intermittent hCG is recommended in the luteal phase since trophic stimulation of corpus luteum from pituitary is lacking in HH cases.
Overall, the treatment results in over 90 % rate of ovulation and a cumulative pregnancy rate of up to 96 % after six cycles [22, 23]. Pulsatile GnRh has also been used successfully for OI in PCOS. In one very large series of 292 anovulatory patients and 900 cycles, there were 130(268) HH women in whom successful ovulation was achieved in 75 % and pregnancy rate in 18 %, per treatment cycle [24]. GnRh was given IV at a dose of 1.25–2.00 micrograms of GnRh every 30–120 min, Maximum cycles required 2.5–5.0 micrograms every 60–90 min. Ovulation and pregnancy rates were higher in all types of HH women as compared to other anovulatory infertilities, like PCOS: only 4 multiple pregnancies occurred (3.8 %) and miscarriage rate was 30 % and even higher in PCOS. No case of OHSS was reported [24].
The main advantage of pulsatile GnRh over gonadotropins is low rate of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) [22–24]. The main disadvantage is the need to keep the pump connected to the body for quite a long time (2–3 weeks) and the necessity to refill the pump frequently. Once very popular, the treatment is less frequently used in general practice now.
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